Single step enantioselective process for the preparation of 3-substituted chiral phthalides

ABSTRACT

The present invention discloses single step, highly enantioselective catalytic oxidative cyclization process for the synthesis of 3-substituted chiral phthalides. In particular, the invention discloses asymmetric synthesis of chiral phthalides via synergetic nitrile accelerated oxidative cyclization of o-cyano substituted aryl alkenes in high yield and enantiomeric excess (ee) in short reaction time. Also, disclosed herein is “one-pot” asymmetric synthesis of biologically important natural compounds having 3-substituted chiral phthalide structural framework in the molecule.

The following specification particularly describes the invention and themanner in which it is to be performed:

FIELD OF INVENTION

The present invention relates to a single step, highly enantioselectivecatalytic oxidative cyclization process for the synthesis of3-substituted chiral phthalides. In particular, the invention relates toasymmetric synthesis of chiral phthalides via synergetic nitrileaccelerated oxidative cyclization of o-cyano substituted aryl alkenes inhigh yield and enantiomeric excess (ee) in short reaction time. Thepresent invention further relates to “one-pot” asymmetric synthesis ofbiologically important natural compounds having 3-substituted chiralphthalide structural framework in the molecule.

BACKGROUND OF THE INVENTION

Chiral phthalides [isobenzofuran-1(3H)-ones] comprising of 5-memberedlactones are found in large number of plant products with broad andpotent biological activities. An article titled “The StructuralDiversity of Phthalides from the Apiaceae” by John J. Beck in J. Nat.Prod., 2007, 70 (5), pp 891-900 discloses the bioactivity of chiralphthalides against several illnesses and physiological conditions,including microbial and viral infections, stroke, tuberculosis.

Due to the biological importance of the 3-substituted chiral phthalides,their molecular architectures have become a platform for new syntheticmethodology development. Over the past two decades, a variety of methodstoward introducing C-3 chirality in phthalides have been establishedwhich include i) transfer hydrogenation of ketone [Tetrahedron Lett.1990, 31, 5509 by Noyori et al]. ii) catalytic enantioselective additionof dialkylzinc reagents to o-phthalaldehyde [J. Org. Chem. 1992, 57, 742by Butsugan et al]. iii) Nickel-catalyzed tandem reaction to asymmetricsynthesis of chiral phthalides [Synlett 2002, 927 by Lin et al]. iv)enantioselective cross alkyne cyclotrimerization in the presence of thecationic complex [Rh^(I){(S)-H₈-binap} [Angew. Chem., Int. Ed. 2004, 43,6510] and rhodium-catalyzed asymmetric one-pot transesterification and[2+2+2] cycloaddition disclosed in M. Org. Lett. 2007, 9, 1307 by Tanakaet al vi) alkynylation of aldehydes (Trost, B. M.; Weiss, A. H. Angew.Chem., Int. Ed. 2007, 46, 7664.), (vii) cyclization approach (Chang, H.T.; Jaganmohan, M.; Cheng, C. H. Chem. Eur. J. 2007, 13, 4356), (viii)organocatalytic aldol-lactonization process (Zhang, H.; Zhang, S.; Liu,L.; Luo, G.; Duan, W.; Wang. W. J. Org. Chem. 2010, 75, 368.) andreductive cyclization of 2-acylarylcarboxylates (Zhang, B.; Xu, M. H.;Lin G. Q. Org. Lett. 2009, 11, 4712).

Ligand accelerated Sharpless Asymmetric Dihydroxylation(AD) of prochiralolefins is widely used for the generation of 1,2-diols.Enantioselectivity is achieved through the addition ofenantiomerically-enriched chiral ligands [(DHQD)2PHAL, (DHQ)2PHAL ortheir derivatives] which are available as prepackaged mixtures (AD-mix aand AD-mix β, AD=asymmetric dihydroxylation) for eitherenantiopreference. The present inventors in their earlier studies havereported a method that employs AD process followed by Co-catalyzed“one-pot” reductive cyclization (CoCl₂—NaBH₄) of nitro cyclic sulfites,which led to the construction of 3-substituted tetrahydroquinolin-3-ols.Further, the said process was extended to prepare synthetically usefulbenzazepines i.e via AD process and catalytically accelerated reductivecyclisation of cyano cyclic sulfites.

In view of the biological importance of 3-substituted chiral phthalidesand the limitations envisaged in the prior art processes for preparationof the same, the inventors of present invention believed that AD processfollowed by catalytic oxidative cyclisation could provide 3-substitutedchiral phthalides in high yield and optical purity in short time.

However, the aforesaid processes employ chiral auxiliaries and expensiveorganometallic reagents that lack broad substrate scope and higherreaction stereo selectivity, also very few process are catalytic andatom economical.

Objective of the Present Invention

The main object of the present invention is to provide highlyenantioselective, single step, catalytic oxidative cyclization methodfor the synthesis of 3-substituted chiral phthalides and theirstructural analogues via Asymmetric Dihydroxylation (AD) process ofo-cyano substituted aryl alkenes with high yield and 99% ee in shortreaction time.

Another object of the present invention is to provide a single step,enantioselective process which is easy to perform, energy saving,ecofriendly, atom economic reaction generating relatively lesseffluents.

SUMMARY OF THE INVENTION

Accordingly, the present invention provides single step, asymmetricdihydroxylation (AD) and nitrile accelerated catalytic oxidativecyclization for synthesis of 3-substituted chiral phthalides of FormulaII, comprising, reacting o-cyano substituted aryl alkenes of Formula Iwith AD-mix-β in presence of a solvent at room temperature rangingbetween 25-35° C. for a period ranging between 3-7 h

-   -   wherein, R1, R2, R3 and R4 are independently same or different        groups selected from hydrogen, C1-C7 straight or branched        alkyl(optionally substituted with halo, hydroxyl, nitro, alkoxy,        amido, nitrile, amine), C2-C7 straight or branched        alkenyl(optionally substituted with halo, hydroxyl, nitro,        alkoxy, amido, nitrile, amine), C2-C7 straight or branched        alkynyls (optionally substituted with halo, hydroxyl, nitro,        alkoxy, amido, nitrile, amine), C1-C7alkoxide, -OTs, -OBn,        halogen, C6-C10 aryls (optionally substituted with halo,        hydroxyl, nitro, alkoxy, amido, nitrile, amine), C3-C6        cycloalkyl (optionally substituted with halo, hydroxyl, nitro,        alkoxy, amido, nitrile, amine), C3-C6 cycloalkenes (optionally        substituted with halo, hydroxyl, nitro, alkoxy, amido, nitrile,        amine), heteroaryls (optionally substituted with halo, hydroxyl,        nitro, alkoxy, amido, nitrile, amine), nitro, —OH, —NR6R7, —CN,        —CONR8R9, —CO—R10; —COOR11;    -   R5 is selected from hydrogen, C1-C7 straight or branched alkyl        (optionally substituted with halo, hydroxyl, nitro, alkoxy,        amido, nitrile, amine), C2-C7 alkyl alkoxy where alkyl is C1-C3        and alkoxy is C1-C4, C6-C10 aryl(optionally substituted with        halo, hydroxyl, nitro, alkoxy, amido, nitrile, amine), —COO R12,        where R12 is C1-C4alkyl;    -   when R5 is —COOR12, R1 and R4 is hydrogen, R2 and R3 together        may represent —O—CH2-O or a phenyl ring (optionally substituted        with halo, hydroxyl, nitro, alkoxy, amido, nitrile, amine), R12        is C1-C4alkyl;    -   when, R5 is C1-C7 straight or branched alkyl (optionally        substituted with halo, hydroxyl, nitro, alkoxy, amido, nitrile,        amine), R1 is —OH, R4 is H, R2 and R3 together represent a        heteroaryl (optionally substituted with halo, hydroxyl, nitro,        alkoxy, amido, nitrile, amine).

In an embodiment of the present invention, wherein the compound ofFormula II comprises;

-   a.    (S)-Ethyl-2-((R)-1,3-dihydro-1-oxoisobenzofuran-3-yl)-2-hydroxyacetate    (IIa-   b.    (S)-Ethyl-2-((R)-1,3-dihydro-5-methoxy-1-oxoisobenzofuran-3-yl)-2-hydroxy    acetate (IIb);-   c.    (S)-Ethyl-2-((R)-1,3-dihydro-5,6-dimethoxy-1-oxoisobenzofuran-3-yl)-2-hydroxy    acetate (IIc);-   d.    (S)-Ethyl-2-((R)-1,3-dihydro-6,7-dimethoxy-1-oxoisobenzofuran-3-yl)-2-hydroxy    acetate (IId);-   e.    (S)-Ethyl-2-((R)-1,3-dihydro-5,7-dimethoxy-1-oxoisobenzofuran-3-yl)-2-hydroxy    acetate (IIe);-   f.    (S)-Ethyl-2-((R)-1,3-dihydro-5,6,7-trimethoxy-1-oxoisobenzofuran-3-yl)-2-hydroxy    acetate (IIf);-   g.    S)-Ethyl-2-((R)-5-(p-toluenesulfonoyloxy)-1,3-dihydro-6-methoxy-1-oxo    iso benzo furan-3-yl)-2-hydroxyacetate (IIg);-   h.    (S)-Ethyl-2-((R)-5-(benzyloxy)-1,3-dihydro-6-methoxy-1-oxoisobenzofuran-3-yl)-2-hydroxyacetate    (IIh);-   i.    (S)-Ethyl-2-((R)-5-fluoro-1,3-dihydro-1-oxoisobenzofuran-3-yl)-2-hydroxy    acetate (IIi);-   j.    (S)-Ethyl-2-((R)-1,3-dihydro-5-nitro-1-oxoisobenzofuran-3-yl)-2-hydroxyacetate    (IIj);-   k. (S)-Ethyl    2-((R)-5-1,3-dihydro-5,6-dioxomethyl-1-oxoisobenzofuran-3-yl)-2-hydroxyacetate    (IIk)-   l. (S)-Ethyl    2-((R)-1,3-dihydro-1-oxonaphtho[2,1-c]furan-3-yl)-2-hydroxyl acetate    (II 1);-   m. (R)-3-(Hydroxymethyl)isobenzofuran-1(3H)-one (IIm);-   n. (R)-3-(Hydroxymethyl)-5-methoxyisobenzofuran-1(3H)-one (IIn);-   o. (R)-3-(Hydroxymethyl)-5,6-dimethoxyisobenzofuran-1(3H)-one (IIo);-   p. (R)-3-(Hydroxymethyl)-6,7-dimethoxyisobenzofuran-1(3H)-one (IIp);-   q. (R)-3-(Hydroxymethyl)-5,7-dimethoxyisobenzofuran-1(3H)-one (IIq);-   r. (R)-3-(Hydroxymethyl)-5,6,7-trimethoxyisobenzofuran-1(3H)-one    (IIr);-   s.    (R)-1,3-Dihydro-1-(hydroxymethyl)-5-methoxy-3-oxoisobenzofuran-6-yl-4-methyl    benzenesulfonate (IIs);-   t.    (R)-5-(Benzyloxy)-3-(hydroxymethyl)-6-methoxyisobenzofuran-1(3H)-one    (IIt);-   u. (R)-5-Fluoro-3-(hydroxymethyl)isobenzofuran-1(3H)-one (IIu);-   v. (R)-3-(Hydroxymethyl)-5,6-dioxomethylisobenzofuran-1(3H)-one    (IIv);-   w. (R)-3-((R)-1-Hydroxy(butyl) isobenzofuran-1(3H)-one (II w)-   x. (R)-3-((R)-1-Hydroxy-2-tertiarybutyldimethylsilylethyl)-5,6    dimethoxyisobenzofuran-1(3H)-one (II x)-   y.    (R)-3-((R)-Hydroxy(phenyl)methyl)-5,6-dimethoxyisobenzofuran-1(3H)-one    (IIy)-   z.    (R)-3-((R)-1-Hydroxyheptyl)-5,6,7-trimethoxyisobenzofuran-1(3H)-one    (IIz)

In one embodiment of the invention, wherein the solvent is selected fromthe group of polar protic solvents such as water, methanol, ethanol,n-propanol, isopropanol, n-butyl alcohol and t-butyl alcohol; polaraprotic solvents such as THF, DMF, DMSO, ethyl acetate; nonpolar organicsolvent such as benzene, toluene, hexane, chloroform either alone or incombination thereof.

In another embodiment of the invention, wherein the solvent used is amixture of t-BuOH, THF, water in the ratio of 0.5:0.5:1.

In yet another embodiment, wherein AD-mix-β contains potassium osmateK₂OsO₂(OH)₄ as the source of osmium tetroxide; potassium ferricyanideK₃Fe(CN)₆, which is the re-oxidant in the catalytic cycle; potassiumcarbonate; and chiral ligand selected from (DHQD)₂PHAL which isphthalazine adduct with dihydroquinidine.

In still another embodiment, wherein yields and enantiomeric excess (ee)of chiral phthalides is in the range of 92-97% and 97-99% respectively.

In still another embodiment, a one pot asymmetric synthesis forpreparation of compounds of general formula (III), wherein the saidprocess comprising the steps of

-   -   (a) preparing compounds of general formula (II) using process as        claimed in claim 1;    -   (b) adding BBr3 and an organic solvent, preferably        dichloromethane followed by stirring at temperature ranging        between 10° C. to 25° C. for a period ranging 6-8 h to obtain        compounds of general formula (III);    -   (c) optionally carrying out Barton-Mccombie deoxygenation of        general formula (II) with 1,1-thiocarbonyl diimidazole in the        presence of dichloromethane as solvent at room temperature        ranging between 25-35° C. for 10-14 h followed by treatment with        tributyltinhydride in the presence of catalytic amount of        azobisisobutyronitrile for 20-40 min to obtain compounds of        general formula (III).

In still another embodiment, wherein compounds of general formula (II)is used is selected from the group consisting of

In still another embodiment, wherein compounds of general formula (III)is used is selected from the group consisting of

BRIEF DESCRIPTION OF FIGURES

FIG. 1 depicts Nosey spectra of IIa

FIG. 2 depicts HSQCGP spectra of Iia

FIG. 3 depicts HPLC chromatogram of IIa

FIG. 4 depicts HPLC chromatogram of IIb

FIG. 5 depicts HPLC chromatogram of IIc

FIG. 6 depicts HPLC chromatogram of Iid

FIG. 7 depicts HPLC chromatogram of IIe

FIG. 8 depicts HPLC chromatogram of IIn

FIG. 9 depicts HPLC chromatogram of IIo

FIG. 10 depicts HPLC chromatogram of IIp

FIG. 11 depicts HPLC chromatogram of IIq

DETAILED DESCRIPTION OF THE INVENTION

As used herein, “atom economic” refers and means to the conversionefficiency of the instant process in terms of all atoms involved(desired products produced) at ambient conditions, leading to lesseffluents.

The present invention relates to a single step, highly enantioselectivecatalytic oxidative cyclization process for the synthesis of3-substituted chiral phthalides from o-cyano substituted aryl alkenesvia synergetic acceleration due to CN and osmate ester groups inproximity positions, that leads to construction of phthalide frameworkin high yield and enantiomeric excess (ee), in short reaction time.

The present invention provides commercially feasible, atom economical,single step, highly enantioselective asymmetric dihydroxylation (AD) vianitrile accelerated oxidative cyclisation of o-cyano substituted arylalkenes for synthesis of 3-substituted chiral phthalides in high yieldand purity in short reaction time.

In an embodiment, the present invention relates to single step,asymmetric dihydroxylation (AD) via synergetic acceleration due to CNand osmate ester groups in proximity positions of o-cyano substitutedaryl alkenes of the general Formula I to obtain 3-substituted chiralphthalides of Formula II in high yield and enantiomeric excess.

wherein, R1, R2, R3 and R4 are independently same or different groupsselected from hydrogen, C1-C7 straight or branched alkyl(optionallysubstituted with halo, hydroxyl, nitro, alkoxy, amido, nitrile, amine),C2-C7 straight or branched alkenyl (optionally substituted with halo,hydroxyl, nitro, alkoxy, amido, nitrile, amine), C2-C7 straight orbranched alkynyls (optionally substituted with halo, hydroxyl, nitro,alkoxy, amido, nitrile, amine), C1-C7alkoxide, -OTs, halogen, C6-C10aryls (optionally substituted with halo, hydroxyl, nitro, alkoxy, amido,nitrile, amine), C3-C6 cycloalkyl (optionally substituted with halo,hydroxyl, nitro, alkoxy, amido, nitrile, amine), C3-C6 cycloalkenes(optionally substituted with halo, hydroxyl, nitro, alkoxy, amido,nitrile, amine), heteroaryls (optionally substituted with halo,hydroxyl, nitro, alkoxy, amido, nitrile, amine), nitro, —OH, —CN;

R5 is selected from hydrogen, C1-C7 straight or branched alkyl(optionally substituted with halo, hydroxyl, nitro, alkoxy, amido,nitrile, amine), C2-C7 alkyl alkoxy where alkyl is C1-C3 and alkoxy isC1-C4, C6-C10 aryl(optionally substituted with halo, hydroxyl, nitro,alkoxy, amido, nitrile, amine), —COO R12, where R12 is C1-C4alkyl;

when R5 is —COOR12, R1 and R4 is hydrogen, R2 and R3 together mayrepresent —O—CH2-O or a phenyl ring (optionally substituted with halo,hydroxyl, nitro, alkoxy, amido, nitrile, amine), R12 is C1-C4alkyl;

when R5 is C1-C7 straight or branched alkyl (optionally substituted withhalo, hydroxyl, nitro, alkoxy, amido, nitrile, amine), R1 is —OH, R4 isH, R2 and R3 together represent a heteroaryl (optionally substitutedwith halo, hydroxyl, nitro, alkoxy, amido, nitrile, amine).

The single step process for the synthesis of 3-substituted chiralphthalides of Formula II in high yield and purity, comprises, reactingo-cyano substituted aryl alkenes of the general Formula I with reagentAD-mix-β in presence of a polar solvent at ambient temperature for about2-8 hours with intramolecular oxidative cyclization to obtain thedesired product.

wherein, R1, R2, R3 R4 and R5 are as described above.

The reagent AD-mix-β used in asymmetric dihydroxylation is a mixture ofpotassium osmate K₂OsO₂(OH)₄ as the source of osmium tetroxide;potassium ferricyanide K₃Fe(CN)₆, which is the re-oxidant in thecatalytic cycle; potassium carbonate; and chiral ligand selected from(DHQD)₂PHAL which is phthalazine adduct with dihydroquinidine.

The solvent for the process is selected from polar protic solvents suchas water, methanol, ethanol, n-propanol, isopropanol, n-butyl alcoholand t-butyl alcohol; polar aprotic solvents such as THF, DMF, DMSO,ethyl acetate; nonpolar organic solvent such as benzene, toluene,hexane, chloroform either alone or in combination thereof in variableratio; preferably a mixture of t-BuOH, THF, water in the ratio of0.5:0.5:1 respectively. The temperature for the process is carried outat ambient temperature for about 2.0 to 8.5 hours.

Asymmetric dihydroxylation is performed in presence of osmium catalystand a stoichiometric oxidant [e.g. K₃Fe(CN)₆ or N-methylmorpholine oxide(NMO)] in a buffered solution to ensure a pH range 8-10, since thereaction proceeds more rapidly under slightly basic conditions.Enantioselectivity is achieved through the addition ofenantiomerically-enriched chiral ligands (DHQD)₂PHAL which isphthalazine adduct with dihydroquinidine.

The intramolecular 5 exo-dig type oxidative cyclisation is assisted bythe presence of a nitrile group which is in proximity to the alkenegroup in the compound of formula I.

The process is given below in Scheme-1.

wherein R¹-R⁵ is as defined above;

The CN-assisted Os-catalysed oxidative cyclisation of compounds ofFormula I(a′-j) to compounds of formula II (a′-j′) is given below inTable 1,

TABLE 1

Yield ee Sr.No R¹ R² R³ R⁴ R⁵ (%)^(a) (%)^(b) a′ H H H OMe CO₂Et 95 99b′ OMe H H OMe CO₂Et 96 99 c′ Cl H H H CO₂Et 97 98 d′ H Cl Cl H CO₂Et 95 98^(c) e′ H H Cl H CO₂Et 94 99 f′ Ph H H H CO₂Et 94  98^(c) g′ H H H HCH₂Ph 95  98^(c) h′ H H H H CH₂OMe 95  97^(c) i′ H OMe H OMe 4-OMeC₆H 96 97^(c) j′ OMe OMe H H CO₂Et 95 98 ^(a)Isolated yield after columnchromatographic purification. ^(b)ee determined by chiral HPLC analysis(see the ESI). ^(c)ee determined by Mosher's ester analysis.

In one of the embodiment, the present invention relates to asymmetricdihydroxylation and nitrile assisted intramolecular 5 exo-dig typeoxidative cyclisation of cyano-ethyl cinnamate, compound of Formula I(a-1);

The process is described below in Scheme 2; wherein the compounds ofFormula I(a-1)) is subjected to single step asymmetric dihydroxylationand nitrile assisted intramolecular oxidative cyclisation using AD-mix 0in presence of a mixture of t-BuOH, THF, water in the ratio of 0.5:0.5:1respectively at room temperature for 6.5 to 8 hours to obtain chiralphthalides of Formula II(a-1)

wherein; R1 is hydrogen and R2-R4 substituents are represented as inbelow Table 2:

Yield ee S. No R² R³ R⁴ (%)^(a) (%)^(b) a H H H 94 99 b OMe H H 95 99 cOMe OMe H 94 99 d H OMe OMe 94 99 e OMe H OMe 94 99 f OMe OMe OMe 92 99g OTs OMe H 93 99 h OBn OMe H 94  99^(c) i F H H 94  99^(c) j NO₂ H H 9399 k —O—CH₂—O— H 95 98 l (E)-ethyl 3-(1-cyanonaphthalen-2-yl)acrylate 94 98^(c) ^(a)Isolated yield after column chromatographic purification.^(b)ee determined by chiral HPLC analysis (see the ESI). ^(c)eedetermined by Mosher's ester analysis.

In yet another embodiment, the process discloses asymmetricdihydroxylation and nitrile assisted intramolecular 5 exo-dig typeoxidative cyclisation of cyano styrenics of Formula I (m-z).

The process is described below in Scheme 3; wherein the compound ofFormula I(m-z) subjected to single step asymmetric dihydroxylation andnitrile assisted intramolecular oxidative cyclisation using AD-mix β inpresence a mixture of t-BuOH, THF, water in the ratio of 0.5:0.5:1respectively, at room temperature for 2.5 to 8 hours to obtain chiralphthalides of Formula II(m-z).

wherein; R1 is hydrogen, and R2-R5 substituents are represented as inbelow Table 3:

Yield S. No R² R³ R⁴ R⁵ (%)^(a) ee (%)^(b) m H H H H 95 99 n OMe H H H95 98 o OMe OMe H H 93 98 p H OMe OMe H 94 99 q OMe H OMe H 94 99 r OMeOMe OMe H 93 98 s OTs OMe H H 95 98^(c) t OBn OMe H H 94 99 u F H H H 9398^(c) v —O—CH₂—O— H H 94 98^(c) w H H H C₃H₇ 93 97 x^(d) OMe OMe HCH₂OTBS 94 97^(c) y^(d) OMe OMe H Ph 94 97^(c) z^(d) OMe OMe H n-C₆H₁₃92 98^(c) ^(a)Isolated yield after column chromatographic purification.^(b)ee determined by chiral HPLC analysis (see the ESI). ^(c)eedetermined by Mosher's ester analysis. ^(d)MeSO₂NH₂ (1equiv.) was usedin the reaction.

In yet another embodiment, the present invention provides “one-pot”asymmetric synthesis of biologically important natural compounds having3-substituted chiral phthalide structural framework in the molecule. Theprocess for the synthesis of bioactive natural compounds (1,2 and 3) andtheir intermediates is given below in Scheme 4 and 5.

The process for the preparation of biological compound 3-butylphthalide(3) is given below in Scheme 4.

In the synthesis, compound 16 is subjected to asymmetric dihydroxylation(AD) and nitrile accelerated oxidative cyclization to obtainintermediate chiral phthalide 21 followed by deoxygenation usingBarton-McCombie reaction to obtain biactive compound 3.

Synthesis of demethyl pestaphthalide of Formula 20, an intermediate inthe biosynthesis of virgatolide-A (FIG. 1, compound 1) and Mattucen Ccompound of formula 2a are given below in

Scheme 5.

The synthesis of bioactive natural compounds and their intermediates ofFormula 3, 20 and 2a-d is carried out in two steps comprising;

-   -   (i) asymmetric dihydroxylation (AD) and nitrile accelerated        oxidative cyclization of o-cyano substituted aryl alkenes of        Formula 16 and 17 to obtain intermediate chiral phthalide        compounds of Formula 18 and 19 respectively;    -   (ii) deoxygenation of compound of formula 21 using        Barton-McCombie reaction to obtain compound of formula 3 or        demethylation with BBr₃ of compounds 18 and 19 to obtain        compounds 20 and 2a respectively.

It is observed that the asymmetric synthesis of all four stereoisomersof Matteucen C and D (2a-d) establishes the stereochemical syn and antirelationship of C-3 and C-8 positions.

The bioactive compound, Virgatolide-A (1) exhibits cytotoxic activityagainst HeLa cells. Compound Mattucen (2a-d) is used for the treatmentof hemostatics and in relieving ostalgia while compound 3-butylphthalideis used as anticonvulsant drug for the treatment of stroke.

In view of above, present invention provides a novel CN-assistedOs-catalyzed oxidative cyclization via AD process of o-cyano substitutedaryl alkenes for the synthesis of wide variety of 3-substituted chiralphthalides and their structural analogues. The so obtained chiralphthalides have excellent enantioselectivities of 97-99% and highproduct yield in the range of 92-97%.

The synergism shown by CN and osmate ester in proximity enhance the rateof the reaction to obtain intramolecular oxidative cyclized compound asa chiral phthalide, the instant synthetic route enables the “one-pot”synthesis of biologically important natural products such as virgatolideA, matteucen C and D, butylphthalide with high optical purities, alsouseful for total synthesis of other bioactive phthalides frameworks.

The present inventors, have concluded that the combination of CN andalkene bond in proximity position enhances the rate of the asymmetriccatalytic oxidative cyclization of a wide range of o-cyano substitutedaryl alkene substrates leading to highly enantioselective synthesis of3-substituted chiral phthalides in short reaction time as disclosed andclaimed in the present invention.

The process of the instant invention, thus, features broad substratescope and good functional group tolerance. Further, the process is easyto perform at ambient conditions, making it energy saving and economic.The process is also eco-friendly, as a single step atom economicreaction generates relatively less effluents. Moreover, the shortreaction time also contributes to saving of energy and process costincluding labour and equipment use.

EXAMPLES

The following examples are given by way of illustration and thereforeshould not be construed to limit the scope of the present invention.

Experimental Study:

-   (A) To account for the mechanistic aspect of the present invention    and to establish the stereochemistry of the cyclized product, the    following experiments were conducted as shown in Scheme 6 below:

It was observed that (i) AD-mix-β of substrates 6, 7 or 10 for 48 hrgave the corresponding cyanodiols 8, 9 or 11 respectively, indicatingthat both CN and C═C groups must be positioned in proximity for CNcoordination assistance to take place; (ii) asymmetricaminohydroxylation of Ia, in addition gave the expected amino alcohol 12(64%) along with diol 13 (30%) (Scheme 6), with no phthalide formation,suggesting that coordination of CN onto imino osmate ester wasthermodynamically less favorable, due to its reduced Lewis acidcharacter. Hence, the inventors of present invention inferred that mereasymmetric dihydroxylation or amino hydroxylation process were notenabled to yield chiral phthalide with high yield and optical purity.The inventors of present invention directed asymmetric dihydroxylationwith specific reaction condition, wherein o-cyano substituted arylalkene of Formula Ia and Iw were subjected to asymmetric dihydroxylationusing AD-mix-β in presence of a mixture of t-BuOH, THF, water in theratio of 0.5:0.5:1 respectively at room temperature which resulted in anintermediate A as shown below in Scheme 7 in which co-ordination of CNto Os(VI) and concurrent attack of osmate ester onto electropositivecarbon of CN helped to accelerate the hydrolysis of osmate esterresulting in 5-exo-dig type cyclization to afford iminoester 15a-b in20% which lead to formation of chiral phthalides. The study clearlyexcludes the possibility of hydrolysis of CN to CO₂H followed bycyclization, whereas addition of benzonitrile as external source ofCN-assistance resulted in no rate enhancement for the AD process.

The mechanism for nitrile-assisted osmium-catalyzed oxidativecyclization is disclosed in scheme 7 as follows;

wherein R¹-R⁴ substituents are as defined above.

(B) A General Experimental Procedure for the Preparation of CyanoCinnamates and Styrenics (Ia-v):

General Experimental Procedure for the Preparation of Cyano Cinnamates(Ia-l)

To a stirred solution of substituted 2-bromobenzaldehydes (50 mmol) inbenzene (100 mL), Ph3P═CHCO2Et (55 mmol) was added. It was refluxed for4 h under N2 atmosphere. After the completion of reaction, benzene wasdistilled out to give the crude product, which was purified by columnchromatography [silica gel (230-400 mesh) and petroleum ether: Ethylacetate (90:10) as eluent] to afford pure product 2-bromo-ethylcinnamates in 94% yield. The product was taken in dry DMF (20 mL) andCuCN (15.6 mmol) was added and refluxed under N2 for 18 h (monitored byTLC). The reaction mixture was cooled to room temperature, diluted withwater (30 mL) and EtOAc (25 mL). The organic layer was separated and theaqueous layer was extracted with EtOAc (2×20 mL). The combined organicextracts were washed with brine and dried over anhyd. Na2SO4 andconcentrated under reduced pressure to give crude products which waspurified by column chromatography [silica gel (230-400 mesh) andpetroleum ether: EtOAc (70:30) as an eluent] gave 2-cyano-ethylcinnamate in 82% yield.

Example 1 (E)-Ethyl 3-(2-cyanophenyl)acrylate (Ia) (substituted2-bromobenzaldehydes: 2-Bromo benzaldehyde)

Yield: 88% (for two steps), colorless solid; mp 60-62° C.; IR (CHCl3):765, 784, 1031, 1184, 1318, 1447, 1480, 1594, 1640, 1712, 2225, 2938,2983 cm-1; 1H NMR (200 MHz, CDCl3): δ 1.36 (t, J=7.3 Hz, 3H), 4.31 (q,J=7.3 Hz, 2H), 6.60 (d, J=16 Hz, 1H), 7.47 (td, J=1.44, 7.55 Hz, 1H),7.62 (td, J=1.44, 7.55 Hz, 1H), 7.70-7.76 (m, 2H), 7.96 (d, J=16 Hz,1H); 13C NMR (CDCl3): δ 14.1, 60.7, 112.5, 116.8, 122.9, 126.8, 129.9,132.8, 133.3, 137.1, 139.1, 165.4; Analysis: C12H11NO2 requires C,71.63; H, 5.51; N, 6.96; found C, 71.59; H, 5.56; N, 6.93%.

Example 2 (E)-Ethyl 3-(2-cyano-5-methoxyphenyl)acrylate (Ib):(substituted 2-bromobenzaldehydes: 5-methoxy, 2-bromo benzaldehyde)

Yield: 86% (for two steps), colorless solid; mp 130-132° C.; IR (CHCl3):728, 868, 1026, 1256, 1490, 1594, 1607, 1640, 1712, 2228, 2853, 29233023 cm-1; 1H NMR (200 MHz, CDCl3): δ 1.36 (t, J=7.08 Hz, 3H), 3.90 (s,3H), 4.29 (q, J=7.08 Hz, 2H), 6.56 (d, J=16 Hz, 1H), 6.97 (dd, J=2.54,8.73 Hz, 1H), 7.15 (d, J=2.54 Hz, 1H), 7.63 (d, J=8.79 Hz, 1H), 7.90 (d,J=16 Hz, 1H); 13C NMR (CDCl3): δ 14.2, 55.6, 60.8, 104.6, 112.1, 116.0,117.3, 123.1, 135.0, 139.4, 162.7, 165.5; Analysis: C13H13NO3 requiresC, 67.52; H, 5.67; N, 6.06. found C, 67.49; H, 5.61; N, 6.01%.

Example 3 (E)-Ethyl 3-(2-cyano-4,5-dimethoxyphenyl)acrylate (1c):(substituted 2-bromobenzaldehydes: 4,5-dimethoxy, 2-bromo benzaldehyde)

Yield: 87% (for two steps), colorless solid; mp 159-161° C.; IR (CHCl3):761, 848, 1094, 1149, 1204, 1326, 1462, 1571, 1594, 1709, 2222, 2984,3018 cm-1; 1H NMR (200 MHz, CDCl3): δ 1.36 (t, J=7.36 Hz, 3H), 3.94 (s,3H), 3.97 (s, 3H), 4.29 (q, J=7.36 Hz, 2H), 6.47 (d, J=16.03 Hz, 1H),7.07 (s, 1H), 7.11 (s, 1H), 7.89 (d, J=16.03 Hz, 1H); 13C NMR (CDCl3): δ14.2, 55.9, 56.2, 60.7, 105.2, 108.2, 114.2, 117.1, 120.7, 131.5, 139.2,150.5, 152.6, 165.8; Analysis: C14H15N04 requires C, 64.36; H, 5.79; N,5.36. found C, 64.32; H, 5.71; N, 5.34%.

Example 4 (E)-Ethyl 3-(2-cyano-3,4-dimethoxyphenyl)acrylate (Id):(substituted 2-bromobenzaldehydes: 3,4-dimethoxy, 2-bromo benzaldehyde)

Yield: 88% (for two steps), colorless solid; mp 145-147° C.; IR (CHCl3):758, 894, 1078, 1138, 1208, 1318, 1326, 1462, 1571, 1594, 1608, 1710,2222, 2984, 3018 cm-1; 1H NMR (200 MHz, CDCl3): δ 1.35 (t, J=7.05 Hz,3H), 3.93 (s, 3H), 4.03 (s, 3H), 4.27 (q, J=7.05 Hz, 2H), 6.48 (d, J=16Hz, 1H), 7.10 (d, J=8.65 Hz, 1H), 7.40 (d, J=8.65 Hz, 1H), 7.83 (d, J=16Hz, 1H); 13C NMR (CDCl3): δ 14.3, 56.1, 60.6, 61.6, 107.9, 114.1, 116.4,120.7, 122.9, 129.7, 139.2, 152.1, 153.5, 165.9; Analysis: C14H15N04requires C, 64.36; H, 5.79; N, 5.36. found C, 64.34; H, 5.71; N, 5.32%.

Example 5 (E)-Ethyl 3-(2-cyano-3,5-dimethoxyphenyl)acrylate (Ie)(substituted 2-bromobenzaldehydes: 3,5-dimethoxy, 2-bromo benzaldehyde)

Yield: 87% (for two steps), colorless solid; mp 119-122° C.; IR (CHCl3):734, 876, 1069, 1128, 1208, 1326, 1326, 1478, 1568, 1594, 1608, 1712,2228, 2958, 3082 cm-1; 1H NMR (200 MHz, CDCl3): δ 1.36 (t, J=7.15 Hz,3H), 3.89 (s, 3H), 3.93 (s, 3H), 4.29 (q, J=7.15 Hz, 2H), 6.47 (d,J=2.13 Hz, 1H), 6.55 (d, J=16 Hz, 1H), 6.73 (d, J=2.13 Hz, 1H), 7.86 (d,J=16 Hz, 1H); 13C NMR (CDCl3): δ 14.3, 55.7, 56.1, 60.8, 94.9, 96.199.4, 103.4, 114.8, 123.3, 139.6, 140.1, 163.4, 163.9, 165.6; Analysis:C14H15N04 requires C, 64.36; H, 5.79; N, 5.36. found C, 64.32; H, 5.71;N, 5.34%.

Example 6 (E)-Ethyl 3-(2-cyano-3,4,5-trimethoxyphenyl)acrylate (If)(substituted 2-bromobenzaldehydes: 3,4,5-trimethoxy, 2-bromobenzaldehyde)

Yield: 88% (for two steps), colorless solid; mp 150-152° C.; IR (CHCl3):669, 703, 749, 940, 1260, 1311, 1573, 1607, 1640, 1708, 2210, 2979, 3016cm-1; 1H NMR (200 MHz, CDCl3): δ 1.36 (t, J=7.15 Hz, 3H), 3.90 (s, 3H),3.96 (s, 3H), 4.06 (s, 3H), 4.28 (q, J=7.15 Hz, 2H), 6.50 (d, J=16 Hz,1H), 6.91 (s, 1H), 7.84 (d, J=16 Hz, 1H); 13C NMR (CDCl3): δ 14.3, 55.8,60.3, 109.1, 115.4, 117.0, 118.5, 126.2, 142.5, 148.5, 151.1, 161.2;Analysis: C15H17N05 requires C, 61.85; H, 5.88; N, 4.81. found C, 61.82;H, 5.79, N 4.75%.

Example 7 5-((E)-2-(Ethoxycarbonyl)vinyl)-4-cyano-2-methoxyphenyl4-methylbenzenesulfonate (Ig): (substituted 2-bromobenzaldehydes: 5tosyl 4 methoxy 2-bromo benzaldehyde)

Yield: 87% (for two steps), colorless solid; mp 150-151° C.; IR (CHCl3):742, 865, 1030, 1128, 1232, 1318, 1329, 1478, 1571, 1594, 1608, 1708,2225, 2982, 3025 cm-1; 1H NMR (200 MHz, CDCl3): δ 1.35 (t, J=6.90 Hz,3H), 2.48 (s, 3H), 3.73 (s, 3H), 4.30 (q, J=6.90 Hz, 2H), 6.54 (d, J=16Hz, 1H), 7.09 (s, 1H), 7.35 (d, J=8.5 Hz, 2H), 7.39 (s, 1H), 7.77 (d,J=8.5 Hz, 2H), 7.91 (d, J=16 Hz, 1H); 13C NMR (CDCl3): δ 14.2, 21.7,56.0, 61.0, 104.5, 110.3, 116.0, 123.8, 128.3, 129.7, 132.6, 137.9,138.4, 139.1, 145.8, 155.6, 165.2; Analysis: C20H19NO6S requires C,59.84; H, 4.77; N, 3.49. found C 59.78; H, 4.69; N, 3.42%.

Example 8 (E)-Ethyl 3-(5-(benzyloxy)-2-cyano-4-methoxyphenyl)acrylate(Ih): (substituted 2-bromobenzaldehydes: 5 benzyloxy 4 methoxy 2-bromobenzaldehyde)

Yield: 86% (for two steps), colorless solid; mp 146-148° C.; IR (CHCl3):738, 825, 1031, 1098, 1234, 1334, 1380, 1467, 1568, 1575, 1608, 1710,2228, 2982, 3034 cm-1; 1H NMR (200 MHz, CDCl3): δ 1.35 (t, J=7.23 Hz,3H), 3.93 (s, 3H), 4.28 (q, J=7.33 Hz, 2H), 5.20 (s, 2H), 6.34 (d,J=15.48 Hz, 1H), 7.08 (s, 2H), 7.34-7.43 (m, 5H), 7.84 (d, J=15.48 Hz,1H); 13C NMR (CDCl3): δ 14.3, 56.2, 60.8, 71.0, 105.5, 110.5, 114.7,117.2, 120.9, 127.3, 128.8, 131.5, 135.4, 139.3, 151.1, 151.8, 165.9;Analysis: C20H19N04 requires C, 71.20; H, 5.68; N, 4.15. found C, 71.14;H, 5.61; N, 4.09%.

Example 9 (E)-Ethyl 3-(5-cyanobenzo[d] [1,3]dioxol-6-yl)acrylate (Ik):(substituted 2-bromobenzaldehydes: 2-bromo pipernal)

Yield: 86%(for two steps), white solid; mp 148-149° C.; IR (CHCl3): 728,878, 1042, 1134, 1256, 1366, 1382, 1478, 1568, 1594, 1608, 1712, 2218,2958, 3082 cm-1; 1H NMR (200 MHz, CDCl3): δ 1.35 (t, J=7.06 Hz, 3H),4.28 (q, J=7.06 Hz, 2H), 6.12 (s, 2H), 6.41 (d, J=15.88 Hz, 1H), 7.05(s, 1H), 7.13 (s, 1H), 7.90 (d, J=15.88 Hz, 1H); 13C NMR (CDCl3): δ14.3, 60.8, 102.8, 105.9, 106.8, 111.8, 116.9, 121.4, 133.9, 138.9,149.2, 151.9, 165.7; Analysis: C13H11N04 requires C, 63.67; H, 4.52; N,5.71. found C 63.59; H, 4.48; N, 5.65%.

Example 10 (E)-Ethyl 3-(1-cyanonaphthalen-2-yl)acrylate (II):(substituted 2-bromobenzaldehydes: 1-bromo naphathaldehyde)

Yield: 88% (for two steps), colorless solid; mp 118-119° C.; IR (CHCl3):784, 865, 989, 1030, 1106, 1210, 1275, 1291, 1319, 1368, 1573, 1607,1712, 2218, 2978, 3084 cm-1; 1H NMR (200 MHz, CDCl3): δ 1.35 (t, J=7.03Hz, 3H), 4.32 (q, J=7.03 Hz, 2H), 6.68 (d, J=16 Hz, 1H), 7.59-7.78 (m,3H), 7.90 (d, J=7.70 Hz, 1H), 8.04 (d, J=8.78 Hz, 1H), 8.19 (d, J=16 Hz,1H), 8.28 (d, J=8.78 Hz, 1H); 13C NMR (CDCl3): δ 14.2, 60.8, 110.8,115.5, 122.1, 123.5, 125.8, 128.3, 129.1, 132.5, 132.9, 137.0, 139.5,165.5; Analysis: C16H13NO2 requires C, 76.48; H, 5.21; N, 5.57. found C,76.42; H, 5.19; N, 5.52%.

General Experimental Procedure for the Preparation of Cyano Styrenes(Im-v)

To a stirred solution of methyltriphenylphosphonium iodide (1.05 eq) inTHF was added n-butyl lithium in hexane (1.05 eq), the solution wasstirred for 30 min at 0° C. and substituted 2-bromo benzaldehydes (1.0eq) in THF was added drop wise via syringe at the same temperature andthe reaction mixture was allowed to stir for 90 min at room temperature(monitored by TLC). The reaction mixture was cooled to 0° C., followedby dilution with sat.NH₄Cl (25 mL) and EtOAc (25 mL). The organic layerwas separated and the aqueous layer was extracted with EtOAc (2×20 mL).The combined organic extracts were washed with brine and dried overanhyd. Na2SO4 and concentrated under reduced pressure to give crudeproducts which was purified by column chromatography [silica gel(230-400 mesh) and petroleum ether:EtOAc (90:10) as an eluent] gave2-bromostyrenes in 86% yield. The product was taken in dry DMF (20 mL)and CuCN (15.6 mmol) was added and refluxed under N2 for 18 h (monitoredby TLC). The reaction mixture was cooled to room temperature, dilutedwith water (30 mL) and EtOAc (25 mL). The organic layer was separatedand the aqueous layer was extracted with EtOAc (2×20 mL). The combinedorganic extracts were washed with brine and dried over anhyd. Na2SO4 andconcentrated under reduced pressure to give crude products which waspurified by column chromatography [silica gel (230-400 mesh) andpetroleum ether: EtOAc (70:30) as an eluent] gave 2-cyano-ethylcinnamates in 86% yield.

Example 11 2-Vinylbenzonitrile (Im): (substituted 2-bromobenzaldehydes:2-bromo benzaldehyde)

Yield: 86% (for two steps), Gum; IR (CHCl3): 752, 839, 962, 1014, 1072,1118, 1202, 1308, 1347, 1368, 1444, 1573, 1607, 1625, 1675, 2215, 2889,2923, 3012 cm-1; 1H NMR (200 MHz, CDCl3): 5.54 (d, J=10.64 Hz, 1H), 5.95(d, J=17.83 Hz, 1H), 7.08 (dd, J=10.64, 17.83 Hz, 1H), 7.34 (td, J=1.28,7.59 Hz, 1H), 7.51-7.70 (m, 3H); 13C NMR (CDCl3): δ 111.0, 117.4, 118.7,125.2, 127.8, 132.5, 132.7, 140.4; Analysis: C9H7N requires C, 83.69; H,5.46; N, 10.84. found C, 83.62; H, 5.41; N, 10.78%.

Example 12 4-Methoxy-2-vinylbenzonitrile (In): (substituted2-bromobenzaldehydes: 5-methoxy, 2-bromo benzaldehyde)

Yield: 84% (for two steps), Gum, IR (CHCl3): 752, 839, 1030, 1083, 1119,1256, 1308, 1347, 1368, 1456, 1573, 1607, 1625, 1668, 2208, 2923, 3081cm-1; 1H NMR (200 MHz, CDCl3): 3.88 (s, 3H), 5.53 (d, J=11.10 Hz, 1H),5.92 (d, J=17.76 Hz, 1H), 6.85 (dd, J=2.30, 8.54 Hz, 1H), 7.03 (dd,J=11.10, 17.76 Hz, 1H), 7.11 (s, 1H), 7.55 (d, J=8.54 Hz, 1H); 13C NMR(CDCl3): δ 55.4, 103.2, 110.4, 114.1, 117.9, 118.7, 132.9, 134.4, 142.5,162.7; Analysis: C10H9NO requires C, 75.45; H, 5.70; N, 8.80. found C,75.41, H 5.67; N, 8.73%.

Example 13 4,5-Dimethoxy-2-vinylbenzonitrile (Io): (substituted2-bromobenzaldehydes: 4,5-dimethoxy, 2-bromo benzaldehyde)

Yield: 88% (for two steps), colorless solid; mp 106-107° C.;IR (CHCl3):752, 839, 936, 1031, 1086, 1119, 1256, 1308, 1378, 1389, 1456, 1575,1612, 1628, 1656, 2210, 2923, 3052 cm-1; 1H NMR (200 MHz, CDCl3): 3.91(s, 3H), 3.97 (s, 3H), 5.45 (d, J=11.08 Hz, 1H), 5.80 (d, J=17.28 Hz,1H), 6.94-7.08 (m, 3H); 13C NMR (CDCl3): δ 55.7, 55.9, 102.7, 106.9,113.5, 116.5, 117.7, 132.5, 134.9, 148.7, 152.5; Analysis: C11H11NO2requires C, 69.83; H, 5.86; N, 7.40. found C, 69.75; H, 5.75; N, 7.39%.

Example 14 2,3-Dimethoxy-6-vinylbenzonitrile (Ip): (substituted2-bromobenzaldehydes: 3,4-dimethoxy, 2-bromo benzaldehyde)

Yield: 86% (for two steps), colorless solid; mp 108-110° C.; IR (CHCl3):748, 840, 936, 1028, 1086, 1119, 1256, 1308, 1378, 1389, 1456, 1575,1612, 1628, 1656, 2202, 2981, 3029 cm-1; 1H NMR (200 MHz, CDCl3): 3.88(s, 3H), 3.90 (s, 3H), 5.53 (d, J=10.99 Hz, 1H), 5.90 (d, J=17.31 Hz,1H), 6.37 (d, J=2.20 Hz, 1H), 6.69 (d, J=2.20 Hz, 1H), 7.01 (dd,J=10.99, 17.31 Hz, 1H); 13C NMR (CDCl3): δ 56.1, 61.5, 106.7, 114.7,116.7, 120.8, 132.4, 133.4, 151.5, 151.7; Analysis: C11H11NO2 requiresC, 69.83, H 5.86; N, 7.40. found C, 69.73; H, 5.78; N, 7.39%.

Example 15 2,4-Dimethoxy-6-vinylbenzonitrile (Iq): (substituted2-bromobenzaldehydes: 3,5-dimethoxy, 2-bromo benzaldehyde)

Yield: 83% (for two steps), colorless solid; mp 76-79° C.; IR (CHCl3):724, 867, 968, 1030, 1086, 1119, 1259, 1308, 1386, 1389, 1456, 1578,1612, 1636, 1656, 2212, 2985, 3029 cm-1; 1H NMR (200 MHz, CDCl3): 3.90(s, 3H), 4.00 (s, 3H), 5.40 (d, J=10.83 Hz, 1H), 5.79 (d, J=17.68 Hz,1H), 6.94 (dd, J=10.83, 17.68 Hz, 1H), 7.07 (d, J=8.55 Hz, 1H), 7.32 (d,J=8.55 Hz, 1H); 13C NMR (CDCl3): δ 55.5, 55.9, 93.6, 97.5, 101.7, 115.5,118.9, 133.1, 143.4, 163.0, 163.8; Analysis: C11H11NO2 requires C,69.83, H 5.86; N, 7.40. found C, 69.79; H, 5.78; N, 7.39%.

Example 16 2,3,4-Trimethoxy-6-vinylbenzonitrile (Ir): (substituted2-bromobenzaldehydes: 3,4,5-trimethoxy, 2-bromo benzaldehyde)

Yield: 87% (for two steps), white solid; mp 102-103° C.; IR (CHCl3):771, 867, 1051, 1105, 1204, 1238, 1257, 1580, 1609, 1753, 2228, 2979,3013 cm-1; 1H NMR (200 MHz, CDCl3): 3.86 (s, 3H), 3.95 (s, 3H), 4.04 (s,3H), 5.48 (d, J=11.28 Hz, 1H), 5.83 (d, J=17.32 Hz, 1H), 6.85 (s, 1H),6.97 (dd, J=11.28, 17.32 Hz, 1H); 13C NMR (CDCl3): δ55.9, 60.8, 61.5,98.7, 103.4, 114.8, 117.8, 132.6, 137.2, 141.1, 155.4, 157.2; Analysis:C12H13NO3 requires C, 65.74; H, 5.98; N, 6.39. found C, 65.72; H, 5.91;N, 6.37%.

Example 17 4-Cyano-2-methoxy-5-vinylphenyl 4-methylbenzenesulfonate (Is)(substituted 2-bromobenzaldehydes: 5 tosyl 4 methoxy 2-bromobenzaldehyde)

Yield: 82% (for two steps), colorless solid; mp 149-150° C.; IR (CHCl3):746, 845, 938, 1034, 1086, 1119, 1256, 1308, 1378, 1389, 1456, 1575,1612, 1628, 1656, 2220, 2978, 3075 cm-1; 1H NMR (200 MHz, CDCl3): 2.48(s, 3H), 3.74 (s, 3H), 5.57 (d, J=10.95 Hz, 1H), 5.86 (d, J=17.62 Hz,1H), 6.93-7.08 (m, 2H), 7.28 (s, 1H), 7.35 (d, J=8.01 Hz, 2H), 7.77 (d,J=8.24 Hz, 2H); 13C NMR (CDCl3): δ 21.7, 55.8, 102.9, 108.9, 116.6,119.7, 127.7, 128.5, 129.6, 132.3, 132.7, 137.7, 141.4, 145.6, 155.5;Analysis: C17H15NO4S requires C, 61.99; H, 4.59; N, 4.25. found C,61.89; H, 4.53; N, 4.23%.

Example 18 4-(Benzyloxy)-5-methoxy-2-vinylbenzonitrile (It):(substituted 2-bromobenzaldehydes: 5 benzyloxy 4 methoxy 2-bromobenzaldehyde)

Yield: 84% (for two steps), colorless solid; mp 111-113° C.; IR (CHCl3):747, 858, 934, 1028, 1065, 1119, 1232, 1308, 1394, 1389, 1456, 1574,1612, 1631, 1656, 2220, 2988, 3086 cm-1; 1H NMR (200 MHz, CDCl3): 3.90(s, 3H), 5.21 (s, 2H), 5.39 (d, J=11.15 Hz, 1H), 5.66 (d, J=17.45 Hz,1H), 6.89-7.04 (m, 2H), 7.10 (s, 1H), 7.32-7.47 (m, 5H); 13C NMR(CDCl3): δ 56.0, 70.8, 103.1, 109.2, 114.0, 116.6, 117.8, 127.2, 128.2,128.6, 132.6, 134.9, 135.7, 149.3, 151.8; Analysis: C17H15NO2 requiresC, 76.96; H, 5.70, N 5.28. found C, 76.91; H, 5.67; N, 5.27%.

Example 19 6-Vinylbenzo[d][1,3]dioxole-5-carbonitrile (Iv): (substituted2-bromobenzaldehydes: 2-bromo pipernal)

Yield: 88% (for two steps), colorless solid; mp 88-91° C.; IR (CHCl3):756, 868, 930, 1038, 1162, 1263, 1359, 1486, 1505, 1604, 1615, 2219,2916, 3018 cm-1; 1H NMR (200 MHz, CDCl3): 5.44 (d, J=11.10 Hz, 1H), 5.77(d, J=17.36 Hz, 1H), 6.07 (s, 2H), 6.95-7.04 (m, 2H), 7.09 (s, 1H); 13CNMR (CDCl3): δ 102.3, 104.0, 104.8, 110.9, 117.2, 117.7, 132.5, 137.5,147.4, 151.8; Analysis: C₁₀H₇NO2 requires C, 69.36; H, 4.07; N, 8.09.found C, 69.34, H 4.02; N, 7.99%.

Experimental Procedure for the Preparation of Cyano Stilbene (1x and Y):

To a stirred solution of benzyl triphenylphosphonium Bromide (1.05 eq)(for Iy) or methyleneOTBs triphenylphosphonium Bromide (1.05 eq) in THFwas added n-butyl lithium in hexane (1.05 eq), the solution was stirredfor 30 min at 0° C. and substituted 2-bromo benzaldehydes (1.0 eq) inTHF was added drop wise via syringe at the same temperature and thereaction mixture was allowed to stir for 3 h at room temperature(monitored by TLC). The reaction mixture was cooled to 0° C., followedby dilution with sat.NH₄Cl (25 mL) and EtOAc (25 mL). The organic layerwas separated and the aqueous layer was extracted with EtOAc (2×20 mL).The combined organic extracts were washed with brine and dried overanhyd. Na2SO4 and concentrated under reduced pressure to give crudeproducts which was purified by column chromatography [silica gel(230-400 mesh) and petroleum ether:EtOAc (90:10) as an eluent] gave2-bromostyrenes in 81 and 88% yield. The product was taken in dry DMF(20 mL) and CuCN (15.6 mmol) was added and refluxed under N2 for 18 h(monitored by TLC). The reaction mixture was cooled to room temperature,diluted with water (30 mL) and EtOAc (25 mL). The organic layer wasseparated and the aqueous layer was extracted with EtOAc (2×20 mL). Thecombined organic extracts were washed with brine and dried over anhyd.

Na2SO4 and concentrated under reduced pressure to give crude productswhich was purified by column chromatography [silica gel (230-400 mesh)and petroleum ether: EtOAc (70:30) as an eluent] gave Ix and Iy in 84and 80% yield respectively.

Experimental Procedure for the Preparation of Cyano Stilbene (1W and Z):

To a stirred solution of Substituted Suflone (1.0 eq) in THF was addedKHMDS (1.1 eq), the solution was stirred for 30 min at −78° C. andsubstituted 2-bromo benzaldehydes (1.0 eq) in THF was added drop wisevia syringe at the same temperature and the reaction mixture was allowedto stir for 3 h at room temperature (monitored by TLC). The reactionmixture was cooled to 0° C., followed by dilution with sat.NH₄Cl (25 mL)and EtOAc (25 mL). The organic layer was separated and the aqueous layerwas extracted with EtOAc (2×20 mL). The combined organic extracts werewashed with brine and dried over anhyd. Na2SO4 and concentrated underreduced pressure to give crude products which was purified by columnchromatography [silica gel (230-400 mesh) and petroleum ether:EtOAc(95:5) as an eluent] gave 2-bromostyrenes in 81 and 89% yield. Theproduct was taken in dry DMF (20 mL) and CuCN (15.6 mmol) was added andrefluxed under N2 for 18 h (monitored by TLC). The reaction mixture wascooled to room temperature, diluted with water (30 mL) and EtOAc (25mL). The organic layer was separated and the aqueous layer was extractedwith EtOAc (2×20 mL). The combined organic extracts were washed withbrine and dried over anhyd. Na2SO4 and concentrated under reducedpressure to give crude products which was purified by columnchromatography [silica gel (230-400 mesh) and petroleum ether: EtOAc(75:25) as an eluent] gave Iw and Iz in 81 and 79% yield respectively.

Example 20 4,5-Dimethoxy-2-styrylbenzonitrile (1y): (substituted2-bromobenzaldehydes: 4,5-dimethoxy, 2-bromo benzaldehyde)

Yield: 83% (for two steps), colorless solid; mp 158-159° C.; IR (CHCl3):696, 761, 1149, 1204, 1326, 1462, 1571, 1594, 2215, 2984, 3023 cm-1; 1HNMR (200 MHz, CDCl3): 3.91 (s, 3H), 4.01 (s, 3H), 7.01-7.17 (m, 3H),7.26-7.42 (m, 4H), 7.54 (d, J=6.91 Hz, 2H); 13C NMR (CDCl3): δ 55.9,102.9, 106.8, 113.6, 118.0, 123.8, 126.7, 128.7, 128.6, 131.2, 134.9,136.1, 148.5, 152.6; Analysis: C17H15NO2 requires C, 76.96; H, 5.70; N,5.28. found C, 76.89; H, 5.57; N, 5.19%.

Example 21 (E)-Ethyl 3-(3-cyanophenyl)acrylate (6)

To a stirred solution of 3-bromobenzaldehyde (50 mmol) in benzene (100mL), Ph₃P═CHCO₂Et (55 mmol) was added. It was refluxed for 4 h under N₂atmosphere. After the completion of reaction, benzene was distilled outto give the crude product, which was purified by column chromatography[silica gel (230-400 mesh) and petroleum ether: Ethyl acetate (90:10) aseluent] to afford pure product 3-bromo-ethyl cinnamates. The product wastaken in dry DMF (20 mL) and CuCN (15.6 mmol) was added and refluxedunder N₂ for 18 h (monitored by TLC). The reaction mixture was cooled toroom temperature, diluted with water (30 mL) and EtOAc (25 mL). Theorganic layer was separated and the aqueous layer was extracted withEtOAc (2×20 mL). The combined organic extracts were washed with brineand dried over anhyd. Na2SO4 and concentrated under reduced pressure togive crude products which was purified by column chromatography [silicagel (230-400 mesh) and petroleum ether: EtOAc (70:30) as an eluent] gave2-cyano-ethyl cinnamate in 93% yield.

Yield: 93%; colorless solid; mp 62-65° C.; IR (CHCl3): 710, 765, 977,1032, 1185, 1278, 1318, 1447, 1480, 1640, 1712, 2225, 2938, 2983 cm-1;1H NMR (200 MHz, CDCl3): δ 1.35 (d, J=7.06 Hz, 3H), 4.28 (d, J=7.06 Hz,2H), 6.48 (d, J=16.11 Hz, 1H), 7.48-7.80 (m, 5H); 13C NMR (CDCl3): δ14.1, 60.5, 113.2, 117.8, 120.8, 129.6, 131.1, 131.6, 132.8, 135.5,141.5, 165.7; Analysis: C12H11NO2 requires C, 71.63; H, 5.51; N, 6.96.found C, 71.59; H, 5.45; N, 6.85%.

Example 22 (E)-Ethyl 3-(4-cyanophenyl)acrylate (7)

To a stirred solution of 4-bromobenzaldehyde (50 mmol) in benzene (100mL), Ph₃P═CHCO₂Et (55 mmol) was added. It was refluxed for 4 h under N₂atmosphere. After the completion of reaction, benzene was distilled outto give the crude product, which was purified by column chromatography[silica gel (230-400 mesh) and petroleum ether: Ethyl acetate (90:10) aseluent] to afford pure product 4-bromo-ethyl cinnamates. The product wastaken in dry DMF (20 mL) and CuCN (15.6 mmol) was added and refluxedunder N₂ for 18 h (monitored by TLC). The reaction mixture was cooled toroom temperature, diluted with water (30 mL) and EtOAc (25 mL). Theorganic layer was separated and the aqueous layer was extracted withEtOAc (2×20 mL). The combined organic extracts were washed with brineand dried over anhyd. Na2SO4 and concentrated under reduced pressure togive crude products which was purified by column chromatography [silicagel (230-400 mesh) and petroleum ether: EtOAc (70:30) as an eluent] gave2-cyano-ethyl cinnamate in 93% yield.

Yield: 93%; colorless solid; mp 68-70° C.; IR (CHCl3): 730, 795, 955,1065, 1194, 1268, 1375, 1445, 1495, 1652, 1721, 2226, 2983 cm-1; 1H NMR(200 MHz, CDCl3): δ 1.35 (d, J=7.15 Hz, 3H), 4.28 (d, J=7.15 Hz, 2H),6.51 (d, J=15.85 Hz, 1H), 7.59-7.71 (m, 5H); 13C NMR (CDCl3): δ 14.1,60.6, 113.2, 117.9, 121.6, 128.2, 132.4, 138.5, 141.8, 165.7; Analysis:C12H11NO2 requires C, 71.63; H, 5.51; N, 6.96. found C, 71.58; H, 5.48;N, 6.88%.

Example 23 (2S,3R)-Ethyl 3-(3-cyanophenyl)-2,3-dihydroxypropanoate (8)

To a 250 mL RB flask was charged K₃Fe(CN)₆ (30 mmol), K₂CO₃ (30 mmol),tert-BuOH (25 mL), THF (25 mL) and H₂O (50 mL). Reaction mixture wasstirred for 10 min and (DHQD)₂-PHAL (1 mol %) and K₂OsO₄ (0.5 mol %)were added and stirred for additional 30 min. To the reaction mixture 6was added and allowed to stir for 24 h at 25° C. After completion ofreaction, sodium bisulphate (5 g) was added slowly at 0° C. Organiclayer was separated and aqueous layer was extracted with ethyl acetate(3×50 ml) combined organic layer was washed with brine (100 mL), driedover sodium sulphate and concentrated under reduced pressure to yieldthe crude products, Flash column chromatography purification [silica gel(230-400 mesh) and petroleum ether: EtOAc (70:30) as an eluent] afforded8 in pure form.

Yield: 93%; Gum; [α]D25-36.06 (c 1.20, CHCl3); IR (CHCl3): 680, 725,954, 1057, 1118, 1214, 1291, 1734, 2229, 2985, 3443 cm-1; 1H NMR (200MHz, CDCl3): δ 1.30 (d, J=7.16 Hz, 3H), 3.26 (d, J=7.51 Hz, 1H), 3.43(d, J=5.89 Hz, 1H), 4.24-4.34 (m, 3H), 5.02 (dd, J=2.38, 7.51 Hz, 1H),7.49 (d, J=7.52 Hz, 1H), 7.57-7.67 (m, 2H), 7.72 (s, 1H); 13C NMR(CDCl3): δ 14.1, 62.3, 73.5, 74.5, 112.2, 118.6, 129.0, 130.2, 130.9,131.3, 141.9, 172.3; Analysis: C12H13N04 requires C, 61.27; H, 5.57; N,5.95. found C, 61.26; H, 5.54; N, 5.89.

Example 24 (2S,3R)-Ethyl 3-(4-cyanophenyl)-2,3-dihydroxypropanoate (9)

To a 250 mL RB flask was charged K₃Fe(CN)₆ (30 mmol), K₂CO₃ (30 mmol),tert-BuOH (25 mL), THF (25 mL) and H₂O (50 mL). Reaction mixture wasstirred for 10 min and (DHQD)₂-PHAL (1 mol %) and K₂OsO₄ (0.5 mol %)were added and stirred for additional 30 min. To the reaction mixture 7was added and allowed to stir for 24 h at 25° C. After completion ofreaction, sodium bisulphate (5 g) was added slowly at 0° C. Organiclayer was separated and aqueous layer was extracted with ethyl acetate(3×50 ml) combined organic layer was washed with brine (100 mL), driedover sodium sulphate and concentrated under reduced pressure to yieldthe crude products, Flash column chromatography purification [silica gel(230-400 mesh) and petroleum ether: EtOAc (70:30) as an eluent] afforded9 in pure form.

Yield: 93%; colorless solid; mp 102-103° C.; [α]D25-36.42 (c 1.10,CHCl3); IR (CHCl3): 685, 765, 1017, 1050, 1105, 1204, 1257, 1752, 2228,2978, 3332 cm-1; 1H NMR (200 MHz, CDCl3): δ 1.31 (d, J=7.06 Hz, 3H),3.03 (d, J=7.63 Hz, 1H), 3.27 (d, J=5.36 Hz, 1H), 4.24-4.35 (m, 3H),5.05 (dd, J=2.38, 7.51 Hz, 1H), 7.49 (d, J=7.52 Hz, 1H), 7.57-7.67 (m,2H), 7.72 (s, 1H); 13C NMR (CDCl3+CD3OD): δ 12.9, 60.6, 73.2, 74.2,110.0, 117.9, 126.7, 131.0, 146.2, 171.4; Analysis: C12H13N04 requiresC, 61.27; H, 5.57; N, 5.95. found C, 61.23; H, 5.52; N, 5.84%.

Example 25 Preparation ofBenzyl(1R,2S)-2-(ethoxycarbonyl)-1-(2-cyanophenyl)-2-hydroxyethylcarbamate(12)

Sodium hydroxide (60 mg, 1.5 mmol) was dissolved in water (4 mL), and0.5 mL of this NaOH solution was transferred to a small vial containingK2OsO2(OH)4 (0.020 mmol for 4 mol %) for later use. To the remainder ofthe NaOH solution were added the carbamate (1.55 mmol) and n-PrOH (2mL). The mixture was stirred for 2 min and placed in a water bath beforetert-butylhypochloritel6 (175 L, 1.52 mmol) was slowly added withvigorous stirring. Then, the resulting solution was sequentially treatedwith a solution of (DHQD)2PHAL (0.025 mmol for 5 mol %) in n-PrOH (1mL), the o-cyano ethylcinnamate (0.50 mmol), the previously preparedsolution of K2OsO2(OH)4, and n-PrOH (1 mL). The reaction mixture wasmonitored by TLC to establish completion, quenched by the addition ofsaturated aqueous sodium sulfite (4 mL) while being cooled in anice-water bath, and stirred for an additional 30 min. The separatedaqueous phase was extracted with EtOAc (3×5 mL), and the combinedorganic extracts were washed with water (3 mL) followed by brine (5 mL),dried over Na2SO4, and concentrated under reduced pressure to give crudeproducts which was purified by column chromatography [silica gel(230-400 mesh) and petroleum ether: EtOAc (60:40) as an eluent] gaveproduct 10 in 64% yield with dr 6:1.Gum; [α]D25-36.06 (c 1.10, CHCl3);IR (CHCl3): 756, 857, 974, 1037, 1095, 1184, 1202, 1275, 1291, 1319,1347, 1368, 1393, 1477, 1573, 1607, 1640, 1716, 2219, 2984, 3023, 3415cm-1; ¹H NMR (200 MHz, CDCl3): δ 1.28 (t, J=7.16 Hz, 3H), 3.34 (d,J=7.51 Hz, 1H), 4.29 (q, J=7.16 Hz, 2H), 4.50 (s, 1H), 5.06 (dd, J=2.38,7.51 Hz, 1H), 5.62 (d, J=8.9 Hz, 1H), 5.85 (d, J=8.9 Hz, 1H), 7.32-7.36(m, 5H), 7.39-7.56 (m, 3H), 7.66-7.77 (m, 1H); ¹³C NMR (CDCl3): δ 14.2,55.3, 60.3, 62.8, 72.5, 111.1, 117.0, 122.0, 128.4, 132.8, 133.2, 142.9,145.8, 155.3, 172.0; Analysis: C12H13N04 requires C, 61.27; H, 5.57; N,5.95. found C, 61.26; H, 5.54; N, 5.89.

Example 26 Ethyl2-(1,3-dihydro-1-iminoisobenzofuran-3-yl)-2-hydroxyacetate (15a):(intermediate)

IR (CHCl3): 687, 728, 975, 1050, 1320, 1385, 1468, 1498, 1678, 1758,2874, 2958, 3413 cm-1; 1H NMR (200 MHz, CDCl3): δ 1.29 (t, J=6.85 Hz,3H), 4.29 (d, J=6.85 Hz, 2H), 4.73 (d, J=2.33 Hz, 1H), 6.10 (s, 1H),7.59 (t, J=6.60 Hz, 2H), 7.75 (t, J=6.60 Hz, 1H), 7.92 (d, J=8.48 Hz,1H); 13C NMR (CDCl3): δ 12.4, 60.9, 69.4, 88.2, 121.5, 123.8, 128.2,128.9, 134.1, 144.4, 167.8, 169.6; ESI-MS: m/z 235.01[M+Na]+.

Example 27 2,4-Dimethoxy-6-styrylbenzonitrile (17)

Yield: 79%; colorless solid; mp 147-148° C.; IR (CHCl3): 694, 831, 953,1045, 1073, 1150, 1203, 1326, 1460, 1570, 1595, 2216 cm-1; 1H NMR (400MHz, CDCl3): δ 3.90 (s, 6H), 6.34 (d, J=2.3 Hz, 1H), 6.80 (d, J=2.3 Hz,1H), 7.20 (d, J=16.4 Hz, 1H), 7.26-7.30 (m, 1H), 7.32-7.38 (m, 3H), 7.55(d, J=7.38 Hz, 2H); 13C NMR (CDCl3): δ 55.6, 56.0, 94.1, 97.4, 101.4,115.7, 124.4, 127.2, 128.8, 133.5, 136.1, 143.4, 163.2, 163.9; Analysis:C17H15NO2 requires C, 76.96; H, 5.70; N, 5.28. found C, 76.92; H, 5.68;N, 5.24%.

Example 28 2,4-Dimethoxy-64(E)-prop-1-enyl)-benzonitrile (16)

Yield: 72%; Gum; IR (CHCl3): 720, 857, 9662, 1036, 1092, 1129, 1260,1318, 1381, 1386, 1450, 1576, 1616, 1629, 1647, 2216, 2982, 3030 cm-1;1H NMR (200 MHz, CDCl3): δ 1.95 (d, J=6.4 Hz, 3H), 3.86 (s, 3H), 3.89(s, 3H), 6.29-6.30 (m, 1H), 6.39-6.46 (m, 1H), 6.60 (d, J=1.8 Hz, 1H),6.69 (d, J=15.5 Hz, 1H); 13C NMR (CDCl3): δ 18.7, 55.5, 55.9, 96.8,101.5, 106.4, 115.7, 126.6, 127.6, 131.4, 144.1, 163.1, 163.8; Analysis:C12H13NO2 requires C, 70.92; H, 6.45; N, 6.89. found C, 70.89; H, 6.40;N, 6.85%.

Example 29 Preparation of(S)-Ethyl-2-((R)-1,3-dihydro-1-oxoisobenzofuran-3-yl)-2-hydroxyacetate(IIa)

To a 250 mL RB flask was charged K₃Fe(CN)₆ (30 mmol), K₂CO₃ (30 mmol),MeSO₂NH₂ (10 mmol), tert-BuOH (25 mL), THF (25 mL) and H₂O (50 mL).Reaction mixture was stirred for 10 min and (DHQD)₂-PHAL (1 mol %) andK₂OsO₄ (0.5 mol %) were added and stirred for additional 30 min. To thereaction mixture I a was added and allowed to stir for 7 h at 25° C.After completion of reaction, sodium bisulphate (5 g) was added slowlyat 0° C. Organic layer was separated and aqueous layer was extractedwith ethyl acetate (3×50 ml) combined organic layer was washed withbrine (100 mL), dried over sodium sulphate and concentrated underreduced pressure to yield the crude products, Flash columnchromatography purification [silica gel (230-400 mesh) and petroleumether: EtOAc (60:40) as an eluent] afforded II a in pure form.

Yield: 94% , colorless solid; mp 146-148° C.; 99% ee by chiral HPLCanalysis (Chiracel OJ-H, n-hexane-iPrOH, 90: 10, 0.5 mL min-1) retentiontime 12.16 (99.65%) and 13.80 (0.35%); [α]D²⁵ −95.65 (c 1.24, CHCl3); IR(CHCl3):762, 856, 968, 1027, 1068, 1078, 1210, 1298, 1349, 1467,1611,1652, 1720, 1768, 2924, 3014, 3440 cm-1; ¹H NMR (200 MHz,CDCl3): δ1.29 (t, J=7.17 Hz, 3H), 3.16 (d, J=5.79 Hz, 1H), 4.30 (q, J=7.17 Hz,2H), 4.66 (dd, J=2.12, 5.81 Hz, 1H), 5.79 (d, J=2.12 Hz, 1H), 7.57 (t,J=7.06 Hz, 2H), 7.68-7.75 (m, 1H), 7.90-7.93 (m, 1H); 13C NMR (CDCl3): δ13.8, 62.4, 70.3, 80.4, 122.0, 125.3, 126.4, 129.3, 134.0, 145.7,169.82, 170.7;HRMS (ESI) calcd for Cl2H12O5 [M+H]+237.0763. found237.0772.

Example 30(S)-Ethyl-2-((R)-1,3-dihydro-5-methoxy-1-oxoisobenzofuran-3-yl)-2-hydroxyacetate(IIb)

Yield: 95%; colorless solid; mp 121-122° C.; 99% ee by chiral HPLCanalysis (Chiracel OJ-H, n-hexane-iPrOH, 90: 10, 1 mL min-1) retentiontime 25.80 (99.55%) and 30.33 (0.45%); [α]D25 −94.49 (c 1.15, CHCl3);IR(CHCl3): 724, 876, 1031, 1084, 1191, 1212, 1278, 1295, 1357, 1398,1445, 1486, 1578, 1607, 1721, 1765, 2984, 3023, 3415 cm-1; 1H NMR (200MHz, CDCl3): δ 1.29 (t, J=7.20 Hz, 3H), 3.14 (brs, 3H), 3.91 (s, 3H),4.29 (q, J=7.20 Hz, 2H), 4.63 (d, J=1.74, 1H), 5.69 (d, J=2.29 Hz, 1H),6.96 (d, J=2.11 Hz, 1H), 7.05 (dd, J=2.11, 8.66 Hz, 1H), 7.80 (d, J=8.66Hz, 1H); 13C NMR (CDCl3): δ 14.0, 55.8, 62.7, 70.5, 79.6, 106.0, 117.0,118.9, 127.1, 148.5, 164.8, 169.5, 170.9; HRMS (ESI) calcd for Cl3H14O6[M+H]+267.0869. found 267.0863.

Example 31(S)-Ethyl-2-((R)-1,3-dihydro-5,6-dimethoxy-1-oxoisobenzofuran-3-yl)-2-hydroxyacetate(IIc)

Yield: 94%; colorless solid; mp 144-146° C.; 99% ee by chiral HPLCanalysis (Chiracel OJ-H, n-hexane-iPrOH, 90: 10, 0.5 mL min-1) retentiontime 23.18 (99.36%) and 27.60 (0.64%); [α]D 25 −95.12 (c 1.12, CHCl3);IR (CHCl3): 758, 945, 1125, 1297, 1507, 1722, 1764, 2925, 3010, 3341cm-1; 1H NMR (200 MHz, CDCl3): δ 1.30 (t, J=7.20 Hz, 3H), 3.20 (d,J=6.23 Hz, 1H), 3.94 (s, 3H), 3.98 (s, 3H), 4.29 (q, J=7.25 Hz, 2H),4.62 (dd, J=2.42, 6.16 Hz, 1H), 5.66 (d, J=2.20 Hz, 1H), 6.93 (s, 1H),7.27 (s, 1H); 13C NMR (DMSOd6):δ 14.4, 56.2, 56.4, 61.2, 70.2, 81.2,105.2, 105.8, 118.2, 141.7, 150.5, 154.8, 170.2, 171.3; HRMS (ESI) calcdfor C14H16O7 [M+H]+297.0974. found 297.0979.

Example 32(S)-Ethyl-2-((R)-1,3-dihydro-6,7-dimethoxy-1-oxoisobenzofuran-3-yl)-2-hydroxyacetate(IId)

Yield: 94%, colorless solid; m.p 110-112° C.; 99% ee by chiral HPLCanalysis (Chiracel OJ-H, n-hexane-iPrOH, 90: 10, 0.5 mL min-1) retentiontime 23.90 (99.44%) and 27.87 (0.56%); [α]D 25 −95.28 (c 1.0, CHCl3); IR(CHCl3): 762, 946, 1132, 1298, 1518, 1728, 1764, 2985, 3034, 3425 cm-1;1H NMR (200 MHz, CDCl3): δ 1.30 (t, J=7.19 Hz, 3H), 3.19 (brs, 1H), 3.91(s, 3H), 4.10 (s, 3H), 4.29 (q, J=7.19 Hz, 2H), 4.57 (s, 1H), 5.65 (d,J=2.09 Hz, 1H), 7.13 (d, J=8.11 Hz, 1H), 7.23 (d, J=8.11 Hz, 1H); 13CNMR (CDCl3): δ 14.1, 56.7, 62.2, 62.6, 70.7, 79.0, 116.4, 118.8, 119.3,138.5, 148.4, 152.9, 167.2, 170.9; HRMS (ESI) calcd for Cl4H16O7[M+H]+297.0974. found 297.0979.

Example 33(S)-Ethyl-2-((R)-1,3-dihydro-5,7-dimethoxy-1-oxoisobenzofuran-3-yl)-2-hydroxyacetate(IIe)

Yield: 94%, colorless solid; mp 154-156° C.; 99% ee by chiral HPLCanalysis (Chiracel OJ-H, n-hexane-iPrOH, 90: 10, 0.5 mL min-1) retentiontime 18.37 (99.60%) and 21.74 (0.40%); [α]D 25 −96.29 (c 1.15, CHCl3);IR (CHCl3): 746, 985, 1130, 1287, 1514, 1723, 1762, 2954, 3085, 3414cm-1; 1H NMR (200 MHz, CDCl3): δ 1.32 (t, J=7.22 Hz, 3H), 3.37 (brs,1H), 3.91 (s, 3H), 3.94 (s, 3H), 4.30 (q, J=7.22 Hz, 2H), 4.61 (s, 1H),5.67 (s, 1H), 6.47 (s, 1H), 6.59 (s, 1H); 13C NMR (CD3OD): δ 14.6, 56.5,56.9, 63.0, 71.9, 82.1, 99.9, 100.3, 108.1, 153.1, 160.9, 168.9, 170.6,172.5; HRMS (ESI) calcd for C14H16O7 [M+H]+297.0974. found 297.0979.

Example 34(S)-Ethyl-2-((R)-1,3-dihydro-5,6,7-trimethoxy-1-oxoisobenzofuran-3-yl)-2-hydroxyacetate(IIf)

Yield: 92%, colorless solid; mp 111-112° C.; [α]D 25 −94.65 (c 1.23,CHCl3); IR (CHCl3): 1012, 1094, 1140, 1254, 1350, 1475, 1602, 1765,2954, 3085, 3408 cm-1; 1H NMR (200 MHz, CDCl3): δ 1.31 (t, J=7.20 Hz,3H), 3.09 (s, 1H), 3.86 (s, 3H), 3.96 (s, 3H), 4.13 (s, 3H), 4.31 (q,J=7.20 Hz, 2H), 4.58 (d, J=2.16 Hz, 1H), 5.58 (d, J=2.16 Hz, 1H), 6.70(s, 1H); 13C NMR (CDCl3): δ 13.9, 56.3, 61.1, 62.0, 62.4, 79.1, 99.6,111.0, 142.0, 143.5, 152.1, 159.7, 167.3, 176.8; HRMS (ESI) calcd forC15H18O8 [M+H]+327.1080. found 327.1072.

Example 35(S)-Ethyl-2-((R)-5-(p-toluenesulfonoyloxy)-1,3-dihydro-6-methoxy-1-oxoisobenzofuran-3-yl)-2-hydroxyacetate(IIg)

Yield: 93%, colorless solid; mp 107-108° C.; [α]D 25 −94.89 (c 1.15,CHCl3); IR (CHCl3): 768, 819, 1025, 1050, 1120, 1180, 1190, 1330, 1374,1494, 1614, 1767, 2924, 3012, 3371 cm-1; 1H NMR (200 MHz, CDCl3): δ 1.27(t, J=7.20 Hz, 3H), 2.48 (s, 3H), 3.07 (s, 1H), 3.78 (s, 3H), 4.26 (q,J=7.20 Hz, 2H), 4.63 (d, J=2.16 Hz, 1H), 5.67 (d, J=2.16 Hz, 1H), 6.99(s, 1H), 7.35 (d, J=8.14 Hz, 2H), 7.49 (s, 1H), 7.76 (d, J=8.14 Hz, 2H);13C NMR (DMSO-d6): δ 14.5, 21.8, 56.7, 61.4, 70.3, 71.6, 81.4, 107.4,118.7, 119.7, 128.6, 130.1, 132.6, 139.5, 145.9, 147.9, 157.0, 168.8,170.9; HRMS (ESI) calcd for C20H20O9S [M+H]+437.0906. found 437.0912.

Example 36(S)-Ethyl-2-((R)-5-(benzyloxy)-1,3-dihydro-6-methoxy-1-oxoisobenzofuran-3-yl)-2-hydroxyacetate(IIh)

Yield: 94%, colorless solid; mp 138-140° C.; [α]D 25 −96.04 (c 1.21,CHCl3); IR (CHCl3): 738, 856, 1025, 1078, 1130, 1184, 1195, 1336, 1395,1494, 1645, 1765, 2942, 3035, 3413 cm-1; 1H NMR (200 MHz, CDCl3): δ 1.28(t, J=7.05 Hz, 3H), 3.04 (d, J=5.93 Hz, 1H), 3.94 (s, 3H), 4.27 (q,J=7.05 Hz, 2H), 4.55 (dd, J=2.59, 5.93 Hz, 1H), 5.22 (d, J=3.59 Hz, 2H),5.61 (d, J=2.08 Hz, 1H), 6.94 (s, 1H), 7.26 (s, 1H), 7.29-7.45 (m, 5H);13C NMR (DMSO-d6): δ 13.7, 55.7, 61.5, 70.3, 70.6, 79.9, 105.2, 105.8,118.5, 127.0, 127.8, 128.3, 135.3, 139.9, 150.8, 153.6, 169.7, 170.4;HRMS (ESI) calcd for C20H20O7 [M+H]+373.1287. found 373.1293.

Example 37(S)-Ethyl-2-((R)-5-1,3-dihydro-5,6-dioxomethyl-1-oxoisobenzofuran-3-yl)-2-hydroxyacetate(II k)

Yield: 95%, colorless solid; mp 150-153° C.; [α]D25 −95.74 (c 1.0,CHCl3); IR (CHCl3): 786, 891, 1015, 1054, 1122, 1183, 1196, 1356, 1395,1489, 1618, 1755, 2942, 3021, 3410 cm-1; 1H NMR (200 MHz, CDCl3): δ 1.31(t, J=7.14 Hz, 3H), 3.10 (brs, 1H), 4.30 (qd, J=1.40, 7.14 Hz, 2H), 4.56(s, 1H), 5.62 (d, J=2.19 Hz, 1H), 6.14 (dd, J=1.40, 4.44 Hz, 2H), 6.89(s, 1H), 7.20 (s, 1H); 13C NMR (CDCl3): δ 14.0, 62.6, 70.4, 79.6, 101.9,102.7, 104.3, 120.4, 142.2, 149.6, 153.7, 169.3, 170.8; Analysis:C13H12O7 requires

C, 55.72; H, 4.32. found C, 55.65; H, 4.29%.

Example 38 (S)-Ethyl 2-((R)-1,3-dihydro-1-oxonaphtho[2,1-c]furan-3-yl)-2-hydroxyl acetate (II 1)

Yield: 94%, colorless solid; mp 107-109° C.; [α]D 25 −95.69 (c 1.15,CHCl3); IR (CHCl3): 784, 865, 989, 1010, 1106, 1210, 1275, 1291, 1319,1368, 1573, 1607, 1750, 2978, 3084, 3457 cm-1; 1H NMR (200 MHz, CDCl3):δ 1.28 (t, J=7.45 Hz, 3H), 3.14 (d, J=6.06 Hz, 1H), 4.31 (q, J=7.45 Hz,2H), 4.74 (dd, J=2.14, 6.06 Hz, 1H), 5.85 (d, J=2.14 Hz, 1H), 7.58 (d,J=8.50 Hz, 1H), 7.63-7.78 (m, 2H), 7.97 (d, J=8.5 Hz, 1H), 8.16 (d,J=8.5 Hz, 1H) 8.97 (d, J=8.5 Hz, 1H); 13C NMR (CDCl3+CD3OD): δ 13.2,61.5, 69.8, 80.3, 118.2, 118.6, 120.3, 122.4, 126.8, 128.0, 128.4,133.0, 135.2, 147.6, 170.4; Analysis: C16H14O5 requires C, 67.13; H,4.93. found C 67.11; H, 4.89%.

Example 39 (R)-3-(Hydroxymethyl)isobenzofuran-1(3H)-one (II m)

To a 250 mL RB flask was charged K₃Fe(CN)₆ (30 mmol), K₂CO₃ (30 mmol),tert-BuOH (25 mL), THF (25 mL) and H₂O (50 mL). Reaction mixture wasstirred for 10 min and (DHQD)₂-PHAL (1 mol %) and K₂OsO₄ (0.5 mol %)were added and stirred for additional 30 min. To the reaction mixture Imwas added and allowed to stir for 5 h at 25° C. After completion ofreaction, sodium bisulphate (5 g) was added slowly at 0° C. Organiclayer was separated and aqueous layer was extracted with ethyl acetate(3×50 ml) combined organic layer was washed with brine (100 mL), driedover sodium sulphate and concentrated under reduced pressure to yieldthe crude products, Flash column chromatography purification [silica gel(230-400 mesh) and petroleum ether: EtOAc (60:40) as an eluent] affordedII m in pure form.

Yield: 95%, colorless solid; mp 101-104° C.; 99% ee by chiral HPLCanalysis (Chiracel OJ-H, n-hexane-iPrOH, 90: 10, 0.5 mL min-1) retentiontime 8.03 (99.36%) and 9.24 (0.64%); [α]D25 −78.12 (c 1.23, CHCl3); IR(CHCl3): 744, 847, 968, 1025, 1067, 1089, 1211, 1288, 1349, 1467, 1607,1640, 1756, 2924, 3012, 3440 cm-1; 1H NMR (200 MHz, CDCl3): 2.61 (s,1H), 3.90 (d, J=11.80 Hz, 1H), 4.14 (d, J=11.80 Hz, 1H), 5.54-5.59 (m,1H), 7.55 (t, J=7.79 Hz, 2H), 7.70 (td, J=1.14, 7.42 Hz, 1H), 7.89 (d,J=7.42 Hz, 1H); ¹³C NMR (CDCl3+CD3OD): δ 61.7, 81.6, 121.6, 124.2,125.6, 128.4, 133.4, 146.8, 170.6; HRMS (ESI) calcd for C9H8O3[M+H]+165.0552. found 165.0559.

Example 40 (R)-3-(Hydroxymethyl)-5-methoxyisobenzofuran-1(3H)-one (II n)

Yield: 95%, colorless solid; mp 137-140° C.; 99% ee by chiral HPLCanalysis (Chiracel OJ-H, n-hexane-iPrOH, 90: 10, 1 mL min-1) retentiontime 27.19 (99.36%) and 39.72 (0.64%); [α]D 25 −78.36 (c 1.12, CHCl3);IR (CHCl3): 728, 868, 1026, 1256, 1490, 1607, 1640, 1749, 2853, 2923,3440 cm-1; ¹H NMR (200 MHz, CDCl3): 2.31 (brs, 1H), 3.84-3.91 (m, 4H),4.06-4.14 (m, 1H), 5.46 (t, J=5.30 Hz, 1H), 6.94 (d, J=2.0 Hz, 1H), 7.04(dd, J=2.0, 8.60 Hz, 1H), 7.80 (d, J=8.60 Hz, 1H); ¹³C NMR(CDCl3+CD3OD): δ 54.9, 62.1, 81.1, 105.6, 116.4, 117.8, 126.1, 149.8,164.5, 170.8; HRMS (ESI) calcd for: C1OH10O4 [M+H]+195.0657. found195.0663.

Example 41 (R)-3-(Hydroxymethyl)-5,6-dimethoxyisobenzofuran-1(3H)-one(IIo)

Yield: 93%, colorless solid; mp 165-167° C.; 99% ee by chiral HPLCanalysis (Chiracel OJ-H, n-hexane-iPrOH, 90: 10, 0.5 mL min-1) retentiontime 23.18 (99.36%) and 27.60 (0.64%); [α]D 25 −77.89 (c 1.0, CHCl3); IR(CHCl3): 698, 828, 956, 102v7, 1056, 1225, 1266, 1309, 1335, 1474, 1508,1612, 1752, 2922, 3023, 3358 cm-1; ¹H NMR (200 MHz, CDCl3): 2.71 (t,J=6.44 Hz, 1H), 3.81-3.90 (m, 1H), 3.93 (s, 3H), 3.99 (s, 3H), 4.04-4.15(m, 1H), 5.42-5.47 (m, 1H), 6.93 (s, 1H), 7.25 (s, 1H); ¹³C NMR(DMSO-d6): δ 56.1, 56.3, 62.4, 81.7, 105.0, 105.8, 117.9, 142.4, 150.4,154.6, 170.6; HRMS (ESI) calcd for: C11H12O5 [M+H]+225.0763. found225.0772.

Example 42 (R)-3-(Hydroxymethyl)-6,7-dimethoxyisobenzofuran-1(3H)-one(IIp)

Yield: 94%, colorless solid; mp 85-88° C.; 99% ee by chiral HPLCanalysis (Chiracel OJ-H, n-hexane-iPrOH, 90: 10, 0.5 mL min-1) retentiontime 18.27 (99.36%) and 20.93

(0.64%); [α]D 25 −78.21 (c 1.0, CHCl3); IR (CHCl3): 698, 798, 956, 1030,1067, 1220, 1328, 1339, 1458, 1605, 1745, 2976, 3012, 3457 cm-1; 1H NMR(200 MHz, CDCl3): 2.24 (brs, 1H), 3.79-3.85 (m, 1H), 3.90 (s, 3H), 3.95(s, 3H), 4.03-4.09 (m, 1H), 5.35-5.39 (m, 1H), 6.42 (s, 1H), 6.48 (s,1H); ¹³C NMR (CDCl3): δ 56.6, 62.0, 63.7, 80.7, 116.8, 118.4, 119.4,139.7, 148.0, 152.5, 168.2; HRMS (ESI) calcd for: Cl1H12O5 [M+H]+225.0718. found 225.0715. HRMS (ESI) calcd for: C11H12O5[M+H]+225.0763.found 225.0772.

Example 43 (R)-3-(Hydroxymethyl)-5,7-dimethoxyisobenzofuran-1(3H)-one(IIq)

Yield: 94%, colorless solid; mp 152-153° C.; 99% ee by chiral HPLCanalysis (Chiracel OJ-H, n-hexane-iPrOH, 90: 10, 0.5 mL min-1) retentiontime 18.27 (99.36%) and 20.40

(0.64%); [α]D 25-78.11 (c 1.0, CHCl3); IR (CHCl3): 695, 765, 950, 1030,1058, 1232, 1331, 1365, 1463, 1615, 1751, 2982, 3010, 3443 cm-1; ¹H NMR(200 MHz, CDCl3): 2.53 (brs, 1H), 3.77-3.88 (m, 1H), 3.91 (s, 3H),3.99-4.04 (m, 3H), 4.10 (s, 1H), 5.40-5.45 (m, 1H), 7.09 (dd, J=084,8.20 Hz, 1H), 7.22 (d, J=8.20 Hz, 1H); ¹³C NMR (CDCl3): δ 54.7, 54.9,62.2, 80.4, 97.6, 98.2, 105.9, 151.7, 158.9, 166.6, 168.9; HRMS (ESI)calcd for: C11H12O5 [M+H]+225.0763. found 225.0772.

Example 44 (R)-3-(Hydroxymethyl)-5,6,7-trimethoxyisobenzofuran-1(3H)-one(II r)

Yield: 92%, colorless solid; mp 178-180° C.; [α]D25-78.05 (c 1.15,CHCl3); IR (CHCl3): 1014, 1097, 1254, 1345, 1483, 1600, 1754, 2947,3017, 3444 cm-1; ¹H NMR (200 MHz, CDCl3): 2.62 (brs, 1H), 3.84-3.90 (m,4H), 3.96 (s, 3H), 4.03-4.09 (m, 1H), 4.13 (s, 3H), 5.35-5.39 (m, 1H),6.69 (s, 1H); ¹³C NMR (CDCl3+CD3OD): δ 56.4, 61.2, 62.1, 63.7, 80.6,99.9, 110.7, 141.8, 144.8, 152.1, 159.7, 168.3; HRMS (ESI) calcd for:C12H14O6 [M+H]+255.0869. found 255.0863.

Example 45(R)-1,3-Dihydro-1-(hydroxymethyl)-5-methoxy-3-oxoisobenzofuran-6-yl-4-methylbenzenesulfonate(II s)

Yield: 93%, colorless solid; mp 152-154° C.; [α]D 25 −77.79 (c 1.18,CHCl3); IR (CHCl3): 734, 849, 973, 103, 1053, 1178, 1345, 1372, 1494,1614, 1755, 2919, 3018, 3437 cm-1; ¹H NMR (200 MHz, CDCl3): 2.24 (brs,1H), 2.48 (s, 3H), 3.80 (s, 3H), 3.92 (dd, J=4.60, 12.36 Hz, 1H), 4.03(dd, J=4.73, 12.36 Hz, 1H), 5.44 (t, J=4.60 Hz, 1H), 6.97 (s, 1H), 7.35(d, J=8.28 Hz, 2H), 7.48 (s, 1H), 7.78 (d, J=8.28 Hz, 2H); ¹³C NMR(CDCl3+CD3OD): δ 20.1, 55.1, 61.5, 81.0, 105.4, 117.4, 119.3, 127.7,128.8, 131.9, 138.9, 145.2, 147.8, 156.6, 169.5; HRMS (ESI) calcd for:C17H16O7S [M+H]+365.0695. found 365.0693.

Example 46(R)-5-(Benzyloxy)-3-(hydroxymethyl)-6-methoxyisobenzofuran-1(3H)-one (IIt)

Yield: 94%, colorless solid; mp 126-128° C.; [α]D 25 −78.22 (c 1.10,CHCl3); IR (CHCl3): 689, 825, 975, 1025, 1076, 1223, 1268, 1312, 1334,1494, 1528, 1621, 1752, 2924, 3032, 3385 cm-1; ¹H NMR (200 MHz, CDCl3):2.31 (brs, 1H), 3.75-3.85 (m, 1H), 3.92 (s, 3H), 3.98-4.06 (m, 1H), 5.22(s, 2H), 5.36-5.41 (m, 1H), 6.92 (s, 1H), 7.28 (s, 1H), 7.32-7.45 (m,5H); ¹³C NMR (CDCl3): δ 56.2, 64.1, 71.1, 81.0, 105.4, 106.6, 118.7,127.3, 128.4, 128.8, 135.6, 140.9, 151.3, 154.0, 170.5; HRMS (ESI) calcdfor: C17H16O5 [M+H]+301.1076,found 301.1072.

Example 47 (R)-3-(Hydroxymethyl)-5,6-dioxomethylisobenzofuran-1(3H)-one(II v)

Yield: 93%, colorless solid; mp 144-145° C.; [α]D 25-78.11 (c 1.20,CHCl3); IR (CHCl3): 698, 852, 957, 1024, 1067, 1232, 1286, 1319, 1343,1484, 1582, 1612, 1766, 2942, 3054, 3389 cm-1; 1H NMR (200 MHz, CDCl3):2.40 (brs, 1H), 3.84 (dd, J=4.05, 12.47 Hz, 1H), 4.06 (dd, J=4.05, 12.47Hz, 1H), 5.41 (m, 1H), 6.13 (d, J=2.33 Hz, 2H), 6.87 (s, 1H), 7.20 (s,1H); 13C NMR (DMSO-d6): δ 62.1, 81.3, 102.8, 103.3, 119.8, 144.5, 149.1,153.3, 169.6; HRMS (ESI) calcd for: C10H8O5 [M+H]+209.0450. found209.0454.

Example 48(R)-3-((R)-Hydroxy(phenyl)methyl)-5,6-dimethoxyisobenzofuran-1(3H)-one(II y)

Yield: 94%, colorless solid; mp 113-115° C.; [α]D 25-79.23 (c 1.15,CHCl3); IR (CHCl3): 756, 857, 974, 1026, 1064, 1158, 1216, 1334, 1604,1743, 2858, 2928, 3430 cm-1; 1H NMR (200 MHz, CDCl3): 3.05 (brs, 1H),3.64 (s, 3H), 3.90 (s, 3H), 4.69 (d, J=7.44 Hz, 1H), 5.47 (d, J=7.44 Hz,1H), 5.85 (s, 1H), 7.20 (s, 1H), 7.34-7.41 (m, 5H); 13C NMR (CDCl3+CD3OD): δ 54.7, 74.4, 83.0, 104.3, 117.4, 126.7, 127.4, 138.2, 140.6,149.8, 153.6, 170.7; Analysis: C17H16O5 requires C, 67.99; H, 5.37.found C, 67.92; H, 5.41%.

Example 49(S)-3-((S)-1-Hydroxyethyl)-5,7-dimethoxyisobenzofuran-1(3H)-one(18)

Yield: 93%; colorless solid; mp 139-140° C.; [α]D25+76.89 (c 1.10,CHCl3); IR (CHCl3): 692, 771, 954, 1036, 1063, 1237, 1329, 1361, 1454,1611, 1725, 2986, 3008, 3447 cm-1; 1H NMR (200 MHz, CDCl3): δ 1.33 (d,J=6.4 Hz, 3H), 2.0 (brs, 1H), 3.88 (s, 3H), 3.94 (s, 3H), 4.09-4.15 (m,1H), 5.17 (d, J=3.99 Hz, 1H), 6.42 (d, J=1.8 Hz, 1H), 6.52 (d, J=1.8 Hz,1H); 13C NMR (CDCl3): δ 18.7, 55.9, 68.6, 82.6, 98.3, 99.1, 107.5,151.9, 159.7, 166.7, 168.0; HRMS (ESI) calcd for: C12H14O5[M+H]+239.0919. found 239.0923.

Example 50 Preparation of Matteucen C

To a 250 mL RB flask charged with K₃Fe(CN)₆ (30 mmol), K₂CO₃ (30 mmol),MeSO₂NH₂ (10 mmol), tert-BuOH (25 mL), THF (25 mL) and H₂O (50 mL).Reaction mixture was stirred for 10 min and (DHQD)₂-PHAL (1 mol %) andK₂OsO₄ (0.5 mol %) were added and stirred for additional 30 min. To thereaction mixture 17 was added and allowed to stir for 6 at 25° C. Aftercompletion of reaction, sodium bisulphate (5 g) was added slowly at 0°C. Organic layer was separated and aqueous layer was extracted withethyl acetate (3×50 ml) combined organic layer was washed with brine(100 mL), dried over sodium sulphate and concentrated under reducedpressure to yield the crude products, Flash column chromatographypurification [silica gel (230-400 mesh) and petroleum ether: EtOAc(60:40) as an eluent] afforded 19 in pure form.

To compound 19 was added BBr₃ and dichloromethane, stirred tillcompletion of the reaction. After the reaction solid was separated andsubjected to reaction to obtain the final product (2a).

(+) Matteucen C (2a).

Yield: 68%; colorless powder; [α]D25+54.18 (c 1.0, MeOH); IR (CHCl3):691, 710, 1169, 1615, 1684, 1725, 3364 cm-1; 1H NMR (500 MHz, DMSO-d6):δ 4.94 (t, J=4.8 Hz, 1H), 5.44 (d, J=4.0 Hz, 1H), 5.72 (d, J=4.8 Hz,1H), 6.23 (d, J=1.8 Hz, 1H), 6.25 (d, J=1.8 Hz, 1H), 7.24-7.36 (m, 5H),10.29 (s, 1H), 10.31 (s, 1H); 13C NMR (CDCl3): δ 72.6, 81.7, 101.1,102.3, 104.2, 126.9, 127.2, 127.6, 140.7, 151.5, 157.6, 163.9, 167.7;HRMS (ESI) calcd for: C15H12O5 [M+H]+273.0763. found 273.0766.

Example 51 3-Butylphthalide (3)

Yield: 86%; Colourless oil; [α]D25 −62.1 (c 1.15, CHCl3, ee=99%);lit.,2i [α]D22-62 (c 4.2, CHCl3, ee=99%); IR (CHCl3): 780, 1346, 1465,1526, 1716, 2932 cm-1; 1H NMR (200 MHz, CDCl3): δ 0.88-0.95 (m, 3H),1.32-1.53 (m, 4H), 1.68-1.86 (m, 1H), 1.97-2.07 (m, 1H), 5.46 (q, J=7.6Hz, 1H), 7.42 (dd, J=1.13, 7.6 Hz, 1H), 7.52 (t, J=7.4 Hz, 1H), 7.66(td, J=1.13, 7.4 Hz, 1H), 7.90 (d, J=7.6 Hz, 1H); 13CNMR (CDCl3): δ13.9, 22.4, 26.9, 34.4, 81.3, 121.9, 125.5, 129.0, 133.9, 150.1, 170.3;HRMS (ESI) calcd for: C12H14O2[M+H]+191.1072. found 191.1069.

Advantages of Present Invention

-   -   1. General preparative method that involves a single-step        CN-assisted oxidative cyclization leading to synthesis of a wide        variety of 3-substituted phthalides and their structural        analogues via asymmetric dihydroxylation of o-cyano cinnamates        and styrenics.    -   2. This reaction is highly practical in the sense that the        products were obtained in excellent yields (up to 95%) and        optical purities (up to 99% ee) in short reaction time and shows        broad substrate scope and good functional group tolerance (28        examples).    -   3. The unusual synergism shown by CN and osmate groups in rate        enhancement of asymmetric dihydroxylation process is unique.    -   4. This method has been successfully demonstrated in the        enantioselective synthesis of three natural products namely        butylphthalide, demethylpestaphthalide and Matteucen C, thus        confirming its structural and stereochemical assignments.    -   5. The present invention provides a process fo r preparation of        highly biological important phthalides in short reaction time        with high yield and high enantioselectivity.

1. Single step, asymmetric dihydroxylation (AD) and nitrile acceleratedcatalytic oxidative cyclization for synthesis of 3-substituted chiralphthalides of Formula II, comprising, reacting o-cyano substituted arylalkenes of Formula with AD-mix-β in presence of a solvent at roomtemperature ranging between 25-35° C. for a period ranging between 3-7 h

wherein, R1, R2, R3 and R4 are independently same or different groupsselected from hydrogen, C1-C7 straight or branched alkyl(optionallysubstituted with halo, hydroxyl, nitro, alkoxy, amido, nitrile, amine),C2-C7 straight or branched alkenyl(optionally substituted with halo,hydroxyl, nitro, alkoxy, amido, nitrile, amine), C2-C7 straight orbranched alkynyls (optionally substituted with halo, hydroxyl, nitro,alkoxy, amido, nitrile, amine), C1-C7alkoxide, -OTs, -OBn, halogen,C6-C10 aryls(optionally substituted with halo, hydroxyl, nitro, alkoxy,amido, nitrile, amine), C3-C6 cycloalkyl (optionally substituted withhalo, hydroxyl, nitro, alkoxy, amido, nitrile, amine), C3-C6cycloalkenes(optionally substituted with halo, hydroxyl, nitro, alkoxy,amido, nitrile, amine), heteroaryls(optionally substituted with halo,hydroxyl, nitro, alkoxy, amido, nitrile, amine), nitro, —OH, —NR6R7,—CN, —CONR8R9, —CO—R10; —COOR11; R5 is selected from hydrogen, C1-C7straight or branched alkyl (optionally substituted with halo, hydroxyl,nitro, alkoxy, amido, nitrile, amine), C2-C7 alkyl alkoxy where alkyl isC1-C3 and alkoxy is C1-C4, C6-C10 aryl(optionally substituted with halo,hydroxyl, nitro, alkoxy, amido, nitrile, amine), —COO R12, where R12 isC1-C4alkyl; when R5 is —COOR12, R1 and R4 is hydrogen, R2 and R3together may represent —O—CH2-O or a phenyl ring(optionally substitutedwith halo, hydroxyl, nitro, alkoxy, amido, nitrile, amine), R12 isC1-C4alkyl; when, R5 is C1-C7 straight or branched alkyl (optionallysubstituted with halo, hydroxyl, nitro, alkoxy, amido, nitrile, amine),R1 is —OH, R4 is H, R2 and R3 together represent a heteroaryl(optionally substituted with halo, hydroxyl, nitro, alkoxy, amido,nitrile, amine).
 2. The single step, asymmetric dihydroxylation processaccording to claim 1, wherein the compound of Formula II comprises; a)(S)-Ethyl-2-((R)-1,3-dihydro-1-oxoisobenzofuran-3-yl)-2-hydroxyacetate(IIa b)(S)-Ethyl-2-((R)-1,3-dihydro-5-methoxy-1-oxoisobenzofuran-3-yl)-2-hydroxyacetate (IIb); c)(S)-Ethyl-2-((R)-1,3-dihydro-5,6-dimethoxy-1-oxoisobenzofuran-3-yl)-2-hydroxyacetate (IIe); d)(S)-Ethyl-2-((R)-1,3-dihydro-6,7-dimethoxy-1-oxoisobenzofuran-3-yl)-2-hydroxyacetate (IId); e)(S)-Ethyl-2-((R)-1,3-dihydro-5,7-dimethoxy-1-oxoisobenzofuran-3-yl)-2-hydroxyacetate (IIe); f)(S)-Ethyl-2-((R)-1,3-dihydro-5,6,7-trimethoxy-1-oxoisobenzofuran-3-yl)-2-hydroxyacetate (IIf); g)S)-Ethyl-2-((R)-5-(p-toluenesulfonoyloxy)-1,3-dihydro-6-methoxy-1-oxoisobenzofuran-3-yl)-2-hydroxyacetate(IIg); h)(S)-Ethyl-2-((R)-5-(benzyloxy)-1,3-dihydro-6-methoxy-1-oxoisobenzofuran-3-yl)-2-hydroxyacetate(IIh); i)(S)-Ethyl-2-((R)-5-fluoro-1,3-dihydro-1-oxoisobenzofuran-3-yl)-2-hydroxyacetate (IIi); j)(S)-Ethyl-2-((R)-1,3-dihydro-5-nitro-1-oxoisobenzofuran-3-yl)-2-hydroxyacetate(IIj); k) (S)-Ethyl2-((R)-5-1,3-dihydro-5,6-dioxomethyl-1-oxoisobenzofuran-3-yl)-2-hydroxyacetate(IIk) l) (S)-Ethyl2-((R)-1,3-dihydro-1-oxonaphtho[2,1-c]furan-3-yl)-2-hydroxyl acetate (II1); m) (R)-3-(Hydroxymethyl)isobenzofuran-1(3H)-one (IIm); n)(R)-3-(Hydroxymethyl)-5-methoxyisobenzofuran-1(3H)-one (IIn); o)(R)-3-(Hydroxymethyl)-5,6-dimethoxyisobenzofuran-1(3H)-one (IIo); p)(R)-3-(Hydroxymethyl)-6,7-dimethoxyisobenzofuran-1(3H)-one(IIp); q)(R)-3-(Hydroxymethyl)-5,7-dimethoxyisobenzofuran-1(3H)-one(IIq); r)(R)-3-(Hydroxymethyl)-5,6,7-trimethoxyisobenzofuran-1(3H)-one (IIr); s)(R)-1,3-Dihydro-1-(hydroxymethyl)-5-methoxy-3-oxoisobenzofuran-6-yl-4-methylbenzenesulfonate (IIs); t)(R)-5-(Benzyloxy)-3-(hydroxymethyl)-6-methoxyisobenzofuran-1(3H)-one(IIt); u) (R)-5-Fluoro-3-(hydroxymethyl)isobenzofuran-1(3H)-one (IIu);v) (R)-3(Hydroxymethyl)-5,6-dioxomethylisobenzofuran-1(3H)-one (IIv); w)(R)-3-((R)-1-Hydroxy(butyl) isobenzofuran-1(3H)-one (II w) x)(R)-3-((R)-1-Hydroxy-2-tertiarybutyldimethylsilylethyl)-5,6 y)(R)-3-((R)-Hydroxy(phenyl)methyl)-5,6-dimethoxyisobenzofuran-1(3H)-one(IIy) z)(R)-3-((R)-1-Hydroxyheptyl)-5,6,7-trimethoxyisobenzofuran-1(3H)-one(IIz)
 3. The process as claimed in claim 1, wherein the solvent isselected from the group of polar protic solvents such as water,methanol, ethanol, n-propanol, isopropanol, n-butyl alcohol and t-butylalcohol; polar aprotic solvents such as THF, DMF, DMSO, ethyl acetate;nonpolar organic solvent such as benzene, toluene, hexane, chloroformeither alone or in combination thereof.
 4. The process as claimed inclaim 4, wherein the solvent used is a mixture of t-BuOH, THF, water inthe ratio of 0.5:0.5:1.
 5. The process as claimed in claim 1, whereinAD-mix-β contains potassium osmate K₂OsO₂(OH)₄ as the source of osmiumtetroxide; potassium ferricyanide K₃Fe(CN)₆, which is the re-oxidant inthe catalytic cycle; potassium carbonate; and chiral ligand selectedfrom (DHQD)₂PHAL which is phthalazine adduct with dihydroquinidine. 6.The process as claimed in claim 1, wherein yields and enantiomericexcess (ee) of chiral phthalides is in the range of 92-97% and 97-99%respectively.
 7. A one pot asymmetric synthesis for preparation ofcompounds of general formula (III), wherein the said process comprisingthe steps of;

a) preparing compounds of general formula (II) using process as claimedin claim 1; b) adding BBr3 and an organic solvent, preferablydichloromethane followed by stirring at temperature ranging between 10°C. to 25° C. for a period ranging 6-8 h to obtain compounds of generalformula (III); c) optionally carrying out Barton-Mccombie deoxygenationof general formula (II) with 1,1-thiocarbonyl diimidazole in thepresence of dichloromethane as solvent at room temperature rangingbetween 25-35° C. for 10-14 h followed by treatment withtributyltinhydride in the presence of catalytic amount ofazobisisobutyronitrile for 20-40 min to obtain compounds of generalformula (III).
 8. A process as claimed in claim 7, wherein compounds ofgeneral formula (II) is used is selected from the group consisting of


9. A process as claimed in claim 7 wherein compounds of general formula(III) is used is selected from the group consisting of